N-arylphenylacetamide derivatives and medicinal compositions containing the same

ABSTRACT

N-Arylphenylacetamide derivatives represented by the following formula [I]: 
                         
(wherein R 1  is C 1-6  alkoxy, etc.; R 2  is hydrogen, —(CH 2 ) m —N(R 6 )(R 7 ) (m is an integer of from 1 to 4; R 6  is hydrogen, C 1-4  alkyl, etc., R 7  is hydrogen, etc.), etc.; R 3  is hydrogen, halogen, etc.; R 4  is C 6-10  alkyl, —Y—R 8  (Y is a single bond, C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, etc., R 8  is aryl, C 3-8  cycloalkyl, C 6-15  polycycloalkyl, etc.), etc.; R 5  is hydrogen, etc.; and X 1  is hydrogen), or pharmaceutically acceptable salts thereof or hydrates or solvates of the same, and a pharmaceutical composition containing the same. These compounds are useful as preventives and/or remedies giving no pain at the early stage of administration, which are efficacious in oral administration and have potent analgesic and antiinflammatory effects.

TECHNICAL FIELD

The present invention relates to an N-arylphenylacetamide derivativebeing useful as an agent for treatment of pain and inflammation, and apharmaceutical composition containing the same.

BACKGROUND ART

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is present in juicesof Capsicum plants, and it has been commonly used as a spice, andfurther, it has been known to exhibit an analgesic effect and anantiinflammatory effect. Capsaicin has been considered to act on aspecific receptor being present in primary afferent sensory nerves(C-fibers: capsaicin-sensitive nerves), whereby it causes a drasticpungency (pain) and further exhibits an analgesic effect and anantiinflammatory effect thereafter. Recently, said receptor has beencloned and named as vanilloid receptor subtype 1 (hereinafter, referredto as VR1) (cf., Nature, 389, 816 (1997)). VR1 has been considered fromits amino acid sequence as an ion channel having six transmembranedomains and showing a high Ca²⁺ permeability, and it is suggested thatVR1 is possibly activated not only by capsaicin-like compounds but alsoby thermal stimuli or protons, and further that VR1 may possibly beinvolved with pain in various clinical conditions. When capsaicin actson VR1 in primary afferent sensory nerves, a cation channel is opened,and the membrane is depolarized so that neuropeptides such as substanceP are released to induce pain. Capsaicin, a pain inducing substance, isactually used in the treatment of painful disorders such as diabeticneuropathy and rheumatic arthritis. The reason for this paradoxical useof capsaicin has been considered that sensory nerves are insensitive(desensitized) to painful stimuli as a result of continuous VR1 cationchannel opening after repeatedly application of capsaicin (cf.,Pharmacol. Rev., 51, 159 (1999)).

At the moment, narcotic analgesics (morphine, etc.) and nonnarcoticanalgesics (NSAIDs, etc.) are commonly used as an analgesic agent.However, the use of narcotic analgesics is strictly restricted, becauseof development of tolerance, dependency or serious side effects thereof.Further, nonnarcotic analgesics are not effective to severe pain, and ithas been known that nonnarcotic analgesics are associated withsignificant rates of upper digestive disorders or liver disorders byprolonged administration thereof. Under the circumstances, it has beendesired to develop an analgesic agent exhibiting a higher analgesiceffect with few side effects. Moreover, since there is no effectiveanalgesic agent for neuropathic pains such as pains caused by diabeticneuropathy, post herpetic neuralgia, trigeminal neuralgia, it has alsobeen desired to develop a novel analgesic agent to treat them.

Capsaicin-like compounds acting on VR1 receptor (VR1 receptor agonists)have been considered to exhibit their effects based on a completelydifferent action mechanism from the existing analgesic agents, i.e.,desensitization of capsaicin-sensitive sensory nerve, and hence, theefficacy of such compounds has greatly been expected for the treatmentof neuropathic pains for which the existing analgesic agents cannot beeffective, or pains induced in various pathologic conditions such asrheumatic arthritis.

Since it is reported that capsazepin, which is an only-known VR1receptor antagonist, exhibits a significant analgesic effect in ananimal pain model (cf., Life Science, 69, 2911 (2001)), VR1 receptorantagonists may also be an agent for treatment of various pains.

The compounds with similar actions of capsaicin may be useful as anagent for treatment of diseases in which primary afferent sensory nerves(C-fibers) are concerned, such as essential pruritus, allergy ornonallergic rhinitis, frequent urination and urinary incontinence withoveractive bladder, stroke, irritable bowel syndrome, respiratorydisorders such as asthma and chronic obstructive pulmonary disease,dermatitis, mucositis, gastric and duodenal ulcers, inflammatory boweldiseases.

Further, since it has been reported that capsaicin exhibits ananti-obesity activity by promoting the hypersecretion of adrenalin (cf.,Pharmacol. Rev., 38, 179 (1986)), capsaicin-like compounds will beuseful as an agent for treatment of obesity.

As capsaicin analogous compounds having an analgesic activity,JP-A-63-295537 (=EP 0282127B, U.S. Pat. No. 5,099,030, U.S. Pat. No.5,045,565) discloses beta-aminoethyl-substituted phenyl compounds,JP-A-4-230257 (=EP 0462933B) discloses N-benzyl-N′-phenyl- and-phenylalkyl-thiourea compounds, and WO 00/16756 disclosesN-acylvanillinamide derivatives. In addition, J. Med. Chem., 36, 2595(1993) discloses with respect to the analgesic effects ofN-(4-hydroxy-3-methoxybenzyl)-4-pentylbenzamide, but it is reported thatthis compound has no analgesic effect. The compounds disclosed in thesepatent publications and literatures are N-benzylamide derivatives orN-benzylthiourea derivatives, but the compounds of the formula (I) asdescribed hereinafter are phenylacetamide derivatives, and therefore,these compounds are different in the chemical structures thereof.

It has been disclosed that the substituted phenylacetamide derivatives(in JP-A-62-48657 (=EP 206609B, U.S. Pat. No. 5,013,759)) and theN-arylalkylphenylacetamide compounds (in JP-A-5-320113 (=EP 0525360B,U.S. Pat. No. 5,242,944) and JP-A-8-283220 (=EP 0721939B, U.S. Pat. No.5,670,546)) exhibit an analgesic effect. Furthermore, GB 2168975discloses an aralkaneamide compound having an analgesic effect. However,these patent publications never specifically disclose theN-arylacetamide derivative of the formula (I) as described below.

WO 99/29674 discloses that the following anilides are compoundsinhibiting the metabolism of retinoic acid.

wherein X is O, etc., R¹ is hydrogen atom, a C₁₋₆ alkyl group, etc., R²is a hydrogen atom, a C₁₋₁₂ alkyl group, a C₂₋₈ alkenyl group, etc., R³is a hydrogen atom, a C₁₋₆ alkyl group, etc., R⁴ is an aryl group, etc.,Het is an unsaturated heterocyclic group selected from a pyrrolyl group,a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolylgroup and a pyrimidinyl group, which may optionally be substituted by anamino, a mercapto, a C₁₋₆ alkyl, a C₁₋₆ alkylthio, or an aryl.

DISCLOSURE OF INVENTION

The present inventors have intensively studied, and have found that theN-arylphenylacetamide derivatives of the following formula (I) exhibit apotent analgesic effect, and hardly cause a pain in the early stage ofadministration, and further they are efficacious in oral administration,and finally they have accomplished the present invention.

An object of the present invention is to provide a novelN-arylphenylacetamide derivative being useful as an agent for treatmentof pain and inflammation. Another object of the present invention is toprovide a pharmaceutical composition containing said compound. Theseobjects and other objects or advantages of the present invention may beapparent to any skilled persons in this art from the followingdisclosure.

The present invention provides an N-arylphenylacetamide derivative ofthe following formula (I), or a pharmaceutically acceptable saltthereof, or a hydrate or solvate thereof (hereinafter, referred to as“the present compound(s)”), a process for preparing the same, and apharmaceutical composition containing the same.

(wherein R¹ is a C₁₋₆ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group, a C₁₋₆ alkylamino group, a di-(C₁₋₆alkyl)-amino group, a C₁₋₆ alkylsulfonylamino group, or anarylsulfonylamino group,

R² is a hydrogen atom, a C₁₋₆ alkylcarbonyl group, an arylcarbonylgroup, —(CH₂)_(m)—N(R⁶)(R⁷), —(CH₂)_(m)OH or —(CH₂)_(q)COOH (in which mis an integer of 2 to 4, q is an integer of 1 to 4, R⁶ is a hydrogenatom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group, an amino-C₂₋₃alkyl group, a formyl group, a C₁₋₃ alkylcarbonyl group, a C₁₋₄alkoxycarbonyl group, an arylcarbonyl group, or an aryl-C₁₋₃alkyloxycarbonyl group, R⁷ is a hydrogen atom, a C₁₋₃ alkyl group, ahydroxy-C₂₋₃ alkyl group, or an amino-C₂₋₃ alkyl group),

R³ is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₄ alkoxygroup, an aryl group, or a formyl group,

R⁴ is a C₆₋₁₀ alkyl group, a group of the following formula (A) or agroup of the following formula (C), and the group of the formula (A) isa group of the formula:—Y—R⁸  (A)[in which Y is a single bond, a C₁₋₃ alkylene group, a C₂₋₃ alkenylenegroup, a C₂₋₃ alkynylene group, —CO(CH₂)_(p)—, a C₂₋₃ alkenylenecarbonylgroup, —O—, —O—(CH₂)₂—, —O—(CH₂)₃—, or —CONH(CH₂)_(p)—, and p is aninteger of 0 to 3, R⁸ is a monocyclic group or a polycyclic groupconsisting of a 5- or 6-membered aromatic ring containing 0 to 3heteroatoms selected from N, O and S, which may optionally besubstituted by 1 to 3 atoms or groups selected from a halogen, a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a C₂₋₆ alkenyl, a C₂₋₆ alkynyl, atrifluoromethyl, a trifluoroethyl, an aryl, an aryl-C₁₋₆ alkyl, a C₁₋₆alkoxy, a trifluoromethoxy, a C₃₋₇ cycloalkyloxy, an aryloxy, anaryl-C₁₋₃ alkyloxy, a C₁₋₆ alkylcarbonyl, a C₃₋₇ cycloalkylcarbonyl, aformyl, a nitro, an amino, a di-(C₁₋₆ alkyl)amino, a cyano, a hydroxy, aC₁₋₃ alkylthio, a C₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, a carboxy-C₁₋₃ alkyl,a C₁₋₄ alkoxycarbonyl, an aryl-C₁₋₃ alkyloxycarbonyl, a carboxy and asulfamoyl; a C₅₋₇ cycloalkenyl group which may optionally be substitutedby 1 to 4 atoms or groups selected from a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl,a halogen, a trifluoromethyl, a C₁₋₄ alkoxycarbonyl, an aryl, anaryl-C₁₋₆ alkyl, a C₁₋₃ alkoxy and a hydroxy; or a group of the formula(B):

(R^(a), R^(b), R^(c) and R^(d) are the same or different and each is ahydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a halogenatom, a trifluoromethyl group, a C₁₋₄ alkoxycarbonyl group, an arylgroup, an aryl-C₁₋₆ alkyl group, a C₁₋₃ alkoxy group or a hydroxy group,or when R^(a) and R^(b) attach to the same carbon atom, then thesegroups may combine to form an oxo group or a thioxo group, or when R^(c)and R^(d) attach to the same carbon atom, then these groups may combinetogether with said carbon atom to form a spiro ring, or 2 or 3 groupsselected from R^(a), R^(b) and R^(c) may combine to form a C₆₋₁₅polycycloalkyl group, and n is an integer of 1 to 6)], and the group ofthe formula (C) is a group of the formula:

(R^(e) and R^(f) are the same or different and each is a hydrogen atom,a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a halogen atom, atrifluoromethyl group, a C₁₋₄ alkoxycarbonyl group, an aryl group, anaryl-C₁₋₆ alkyl group, a C₁₋₃ alkoxy group or a hydroxy group, or whenR^(e) and R^(f) attach to the same carbon atom, then these groups maycombine together with said carbon atom to form a spiro ring, and Z is acarbon atom, an oxygen atom or a sulfur atom),

R⁵ is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, atrifluoromethyl group, a C₁₋₃ alkoxy group, a trifluoromethoxy group, acyano group, a nitro group, an amino group, a hydroxy group, a carboxylgroup, a C₁₋₆ alkylcarbonyloxymethyl group, or an aryl group,

or R⁴ and R⁵ may combine together with the benzene ring to which theybond, and form a tetralone ring or an indole ring, which is substitutedby one group selected from a C₁₋₈ alkyl, a C₁₋₈ alkenyl, an aryl-C₁₋₃alkyl, a C₃₋₇ cycloalkyl-C₁₋₃ alkyl, an arylsulfonyl, a C₁₋₈ alkylidene,a C₁₋₈ alkenylidene, an aryl-C₁₋₃ alkylidene and a C₃₋₇ cycloalkyl-C₁₋₃alkylidene,

X¹ is a hydrogen atom,

excluding the compound of the formula (I) wherein R⁴ is —Y—R⁸ at thepara-position (in which Y is a C₁₋₃ alkylene group or a C₂₋₃ alkenylenegroup, and R⁸ is an unsaturated heterocyclic group selected from apyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolylgroup, a tetrazolyl group, and a pyrimidyl group, which may optionallybe substituted by an amino, a C₁₋₆ alkyl, an aryl or a C₁₋₃ alkylthiogroup).

The pharmaceutically acceptable salt of the compound of the formula (I)includes a pharmaceutically acceptable acid addition salt of thecompound of the formula (I) having a group being capable of producing anacid addition salt within the structure thereof, or a pharmaceuticallyacceptable salt with a base of the compound of the formula (I) having agroup being capable of producing a salt with a base within the structurethereof. Suitable acid addition salts are, for example, a salt with aninorganic acid such as hydrochloride, hydrobromide, hydroiodide,sulfate, perchlorate, phosphate, etc., and a salt with an organic acidsuch as oxalate, malonate, maleate, fumarate, lactate, malate, citrate,tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate,p-toluenesulfonate, trifluoromethanesulfonate, etc., an amino acid saltsuch as glutamate, aspartate, etc. Suitable examples of a salt with abase are an alkali metal salt or an alkaline earth metal salt (e.g.,sodium salt, potassium salt, calcium salt, etc.), a salt with an organicbase (e.g., pyridine salt, triethylamine salt, etc.), a salt with anamino acid (e.g., a salt with lysine, arginine, etc.).

The compound of the formula (I) or a salt thereof may exist in the formof a hydrate and/or a solvate, and these hydrates and/or solvates arealso included in the compounds of the present invention. Further, thecompound of the formula (I) may optionally have one or more asymmetriccarbon atoms, and may have isomerism. Therefore, the compound of theformula (I) may exist in the form of several stereoisomers, and thesestereoisomers, a mixture thereof and racemic compounds thereof are alsoincluded in the compounds of the present invention.

The terms in the present specification are explained below.

In the present specification, the number of the carbon atoms is definedsuch as “C₁₋₆ alkylcarbonyl”, and the number of the carbon atoms isapplied to only the group or moiety immediately following thereto.Therefore, in the above case, since C₁₋₆ indicate only the number ofcarbon atom of the alkyl, and hence, “ C₁ alkylcarbonyl” means acetyl.

The “halogen atom” is fluorine atom, chlorine atom, bromine atom, andiodine atom.

The “C₁₋₆ alkyl group” may be either a straight chain alkyl group or abranched chain alkyl group, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, and the equivalents thereof. The “C₆₋₁₀ alkyl group” may beeither a straight chain alkyl group or a branched chain alkyl group, forexample, octyl, nonyl, decyl, and the equivalents thereof.

The “C₂₋₆ alkenyl group” includes either a straight chain alkenyl groupor a branched chain alkenyl group, having at least one double bond, forexample, vinyl, allyl, 1-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-,3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, andthe equivalents thereof.

The “C₂₋₆ alkynyl group” may be either a straight chain alkynyl group ora branched chain alkynyl group, having at least one triple bond, forexample, ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butynyl,1-methyl-2-propynyl, and the equivalents thereof.

The “C₃₋₇ cycloalkyl group” is, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the equivalents thereof.

The “C₅₋₇ cycloalkenyl group” is, for example, cyclopenten-1-yl,cyclohexen-1-yl, cyclohepten-5-yl, and the equivalents thereof.

The “aryl group” includes either an unsubstituted aryl group or asubstituted aryl group, and the unsubstituted aryl group is a monocyclicor polycyclic group consisting of 5- or 6-membered aromatic ring, whichcontains 0 to 3 heteroatoms selected from N, O and S, and when it is apolycyclic group, then it has at least one aromatic ring. Examples ofthe unsubstituted aryl group are phenyl, naphthyl, fluorenyl, antholyl,biphenylyl, tetrahydronaphthyl, indanyl, phenanthryl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,quinolyl, benzo[d]-1,3-dioxolanyl, benzo[b]-1,4-dioxolanyl,benzo[d]oxazolyl, benzo[b]-1,4-dioxepinyl, benzo[d]thiazolyl,benzo[b]thiophenyl, benzo[b]furanyl, benzimidazolyl,1H-imidazo[4,5-b]-pyridyl, tetrahydroquinolyl,tetrahydro-1,8-naphthyridinyl, dibenzo[b,d]-furanyl, and the equivalentsthereof.

The substituted aryl group is the above-mentioned unsubstituted arylgroups, which are substituted by 1 to 3 atoms or groups selected from ahalogen, a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, a C₁₋₃ alkoxy, atrifluoromethyl, a trifluoromethoxy, a C₁₋₃ alkylthio, a cyano, ahydroxy, a carboxyl, a C₁₋₃ alkoxycarbonyl, a C₁₋₃ alkylcarbonyl, aformyl, a nitro, an amino, a C₁₋₃ alkylamino, a phenyl, a benzyl, and abenzyloxy, and examples of the substituted aryl group are 2-, 3- or4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-isopropylphenyl,2-, 3- or 4-tert-butylphenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or4-chlorophenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or4-methoxyphenyl, 2-, 3- or 4-difluoromethoxyphenyl, 2-, 3- or4-trifluoromethoxyphenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or4-hydroxyphenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or4-methoxycarbonylphenyl, 2-, 3- or 4-acetylphenyl, 2-, 3- or4-formylphenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-cyclohexylphenyl,2-, 3- or 4-methylthiophenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or4-phenylphenyl, 2-, 3- or 4-benzylphenyl, 2-, 3- or 4-benzyloxyphenyl,2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,3-dimethylphenyl,2,4-dimethylphenyl, 3,4-dimethylphenyl, 2-fluoro-4-hydroxyphenyl,4-hydroxy-3-methoxyphenyl, 4-hydroxy-3,5-dimethoxyphenyl,2,4,6-trimethylphenyl, 2-aminopyridyl, 2-methylaminopyridyl,5-methyl-pyrimidinyl, 1-methyl-2-pyrrolyl,2-acetylamino-4-methyl-5-thiazolyl, 1-methylbenzimidazol-2-yl,4-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methyl-2-furyl,5-methylbenzo[d]-1,3-dioxolanyl, 3,5-dimethyl-4-isoxazolyl, and theequivalents thereof.

The “C₁₋₃ alkylene group” may be either a straight chain alkylene groupor a branched chain alkylene group, and examples thereof are —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂— and the equivalents thereof.

The “C₂₋₃ alkenylene group” may be either a straight chain alkenylenegroup or a branched chain alkenylene group, having at least one doublebond, and examples thereof are —CH═CH—, —CH₂—CH═CH—, and the equivalentsthereof.

Examples of the “C₂₋₃ alkynylene group” are —C≡C—, —CH₂—C≡C—, and—C≡C—CH₂—.

Examples of complexes consisting of the alkyl, cycloalkyl, alkenyl oralkynyl moiety, or the aryl, alkylene, alkenylene or alkynylene moiety,where the number of carbon atom of these moieties are defined, are oneswherein the above mentioned examples for each group are respectivelyapplied to the relevant moiety. For example, examples of the C₁₋₆ alkoxygroup are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and the equivalentsthereof.

The group of the formula (B):

is, for example, an optionally substituted C₃₋₈ cycloalkyl group, anoptionally substituted C₆₋₁₅ polycycloalkyl group and an optionallysubstituted spiro ring. The unsubstituted C₃₋₈ cycloalkyl group is, forexample, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group.The substituted C₃₋₈ cycloalkyl group is, for example, a cyclopentylgroup, a cyclohexyl group, or a cycloheptyl group, which is substitutedby 1 to 4 atoms or groups selected from a methyl, an ethyl, a propyl, anisopropyl, a tert-butyl, a fluorine, a trifluoromethyl, amethoxycarbonyl, a phenyl, a methoxy and a hydroxy; a 3-oxocyclopentylgroup; a 3-oxocyclohexyl group; a 3-oxocycloheptyl group, and theequivalents thereof.

The “C₆₋₁₅ polycycloalkyl group” means “groups derived from a C₆₋₁₅condensed polycyclic saturated hydrocarbons” and “groups derived from aC₆₋₁₅ cross-linked saturated hydrocarbons”. Examples of theunsubstituted C₆₋₁₅ polycycloalkyl group are as described below, and theequivalents thereof are also included therein.

The spiro ring means a 3- to 7-membered one optionally having 0 to 2heteroatoms selected from O, N and S. Examples of the unsubstitutedspiro ring are as described below, and the equivalents thereof are alsoincluded therein.

The “C₁₋₈ alkylidene” is, for example, a methylidene, an ethylidene, andthe equivalents thereof.

Examples of the group of the following formula (C):

are as described below, and the equivalents thereof are also includedtherein.

The preferable compounds of the present invention areN-arylphenylacetamide derivatives of the formula (I) or apharmaceutically acceptable salt thereof, or a hydrate or solvatethereof, where R¹ is a C₁₋₄ alkoxy group, a hydroxy group, a halogenatom, a nitro group, an amino group, a C₁₋₆ alkylsulfonylamino group, oran arylsulfonylamino group,

R² is a hydrogen atom, a C₁₋₆ alkylcarbonyl group, an arylcarbonylgroup, —(CH₂)₂—N(R⁶¹)(R⁷¹) (in which R⁶¹ is a hydrogen atom, a C₁₋₃alkyl group, a hydroxy-C₂₋₃ alkyl group, an amino-C₂₋₃ alkyl group, aformyl group, a C₁₋₃ alkylcarbonyl group, a C₁₋₄ alkoxycarbonyl group,an arylcarbonyl group or an aryl-C₁₋₃ alkyloxycarbonyl group, and R⁷¹ isa hydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group, or anamino-C₂₋₃alkyl group),

R⁴ is a C₆₋₁₀ alkyl group, the group of the above-mentioned formula (C),or the group of the above-mentioned formula (A) (provided that in theabove-mentioned formula (A), Y is a single bond, a C₁₋₃ alkylene group,a C₂₋₃ alkenylene group, a C₂₋₃ alkynylene group, —CO(CH₂)_(p′)—, a C₂₋₃alkenylenecarbonyl group, —O— or —O—(CH₂)₂—, p′ is an integer of 0 to 2,R⁸ is a monocyclic or polycyclic group consisting of a 5- or 6-memberedaromatic ring containing 0 to 3 heteroatoms selected from N, O and S,which may optionally be substituted by 1 to 3 atoms or groups selectedfrom a halogen, a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, a trifluoromethyl, atrifluoroethyl, an aryl, an aryl-C₁₋₃ alkyl, a C₁₋₃ alkoxy, atrifluoromethoxy, an aryloxy, a C₁₋₃ alkylcarbonyl, a C₃₋₇cycloalkylcarbonyl, a formyl, a nitro, a cyano, a hydroxy, a C₁₋₃alkylthio, a C₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, a carboxy-C₁₋₃ alkyl, aC₁₋₄ alkoxycarbonyl, an aryl-C₁₋₃ alkyloxycarbonyl and a carboxyl; aC₅₋₇ cycloalkenyl group which may optionally be substituted by 1 to 4atoms or groups selected from a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, ahalogen, a trifluoromethyl, a C₁₋₄ alkoxycarbonyl, an aryl, an aryl-C₁₋₆alkyl, a C₁₋₃ alkoxy and a hydroxy; or the group of the above-mentionedformula (B)),

R³, R⁵ and X¹ are as defined above.

More preferable compounds are N-arylphenylacetamide derivatives of theformula (I) or a pharmaceutically acceptable salt thereof, or a hydrateor solvate thereof, wherein R⁴ is located at the meta-position withrespect to the group —N(X¹)—, and R¹, R², R³, R⁴, R⁵ and X¹ are asdefined above.

Further preferable compounds are N-arylphenylacetamide derivatives ofthe following formula (I′) or a pharmaceutically acceptable saltthereof, or a hydrate or solvate thereof.

wherein R^(1′) is a C₁₋₄ alkoxy group, a hydroxy group, a halogen atom,a nitro group, an amino group, a C₁₋₆ alkylsulfonylamino group or anarylsulfonylamino group,

R²′ is a hydrogen atom, a C₁₋₆ alkylcarbonyl group, an arylcarbonylgroup or —(CH₂)₂—N(R^(6′))(R^(7′)), in which R^(6′) is a hydrogen atom,a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group, an amino-C₂₋₃ alkylgroup, a formyl group, or an aryl-C₁₋₃ alkyloxycarbonyl group, andR^(7′) is a hydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkylgroup, or an amino-C₂₋₃ alkyl group,

R^(3′) is a hydrogen atom, a halogen atom, a C₁₋₄ alkyl group or an arylgroup,

R^(4′) is a C₆₋₁₀ alkyl group, a group of the following formula (A′), ora group of the following formula (C′), in which the group of the formula(A′) is a group of the formula:—Y′—R^(8′)  (A′)[in which Y′ is a single bond, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CH═CH—,—C≡C—, —CO—, —COCH₂—, —CO(CH₂)₂—, —COCH═CH—, —O— or —O(CH₂)₂—, andR^(8′) is a monocyclic or polycyclic group consisting of a 5- or6-membered aromatic ring containing 0 to 3 heteroatoms selected from N,O and S, which may optionally be substituted by 1 to 3 atoms or groupsselected from a halogen, a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, atrifluoromethyl, a trifluoroethyl, an aryl, an aryl-C₁₋₃ alkyl, a C₁₋₃alkoxy, a trifluoromethoxy, an aryloxy, a C₁₋₃ alkylcarbonyl, a C₃₋₇cycloalkylcarbonyl, a nitro, a cyano, a hydroxy, a C₁₋₃ alkylthio, aC₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, a carboxy-C₁₋₃ alkyl, a C₁₋₄alkoxycarbonyl and a carboxy; a C₅₋₇ cycloalkenyl group which mayoptionally be substituted by 1 to 4 atoms or groups selected from a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a fluorine, a trifluoromethyl, an aryl, a C₁₋₃alkoxy and a hydroxy; or a group of the formula (B′):

(R^(a′), R^(b′), R^(c′) and R^(d′) are the same or different and each isa hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorineatom, a trifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group or ahydroxy group, or when R^(a′) and R^(b′) attach to the same carbon atom,then these groups may combine to form an oxo group, or when R^(c′) andR^(d′) 0 attach to the same carbon atom, then these groups may combinetogether with said carbon atom to form a spiro ring, or 2 or 3 groupsselected from R^(a′), R^(b′) and R^(c′) may combine to form a C₆₋₁₅polycycloalkyl group, and n′ is an integer of 1 to 5)], and the group ofthe formula (C′) is a group of the formula:

(R^(e′) and R^(f′) are the same or different and each is a hydrogenatom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorine atom, atrifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group or a hydroxygroup, or R^(e′) and R^(f′) attach to the same carbon atom, then thesegroups may combine together with said carbon atom to form a spiro ring,and Z is a carbon atom, an oxygen atom or a sulfur atom),

R^(5′) is a hydrogen atom, a halogen atom, a C₁₋₃ alkyl group, atrifluoromethyl group, a C₁₋₃ alkoxy group, a trifluoromethoxy group oran aryl group,

or R^(4′) and R^(5′) may combine together with the benzene ring to whichthey bond, and form a tetralone ring or an indole ring, which issubstituted by one group selected from a C₁₋₈ alkyl, an aryl-C₁₋₃ alkyl,a C₃₋₇ cycloalkyl-C₁₋₃ alkyl, an arylsulfonyl, a C₁₋₈ alkylidene, a C₁₋₈alkenylidene, an aryl-C₁₋₃ alkylidene and a C₃₋₇ cycloalkyl-C₁₋₃alkylidene.

The compound of the above formula (I′) includes N-arylphenylacetamidederivatives of the following formula (Ia), or a pharmaceuticallyacceptable salt thereof, or a hydrate or solvate thereof.

wherein R¹¹ is a C₁₋₄ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group, a C₁₋₆ alkylsulfonylamino group or anarylsulfonylamino group,

R²¹ is a hydrogen atom, a C₁₋₆ alkylcarbonyl group, an arylcarbonylgroup or —(CH₂)₂—N(R⁶²)(R⁷²), in which R⁶² is a hydrogen atom, a C₁₋₃alkyl group, a hydroxy-C₂₋₃ alkyl group, an amino-C₂₋₃ alkyl group, aformyl group, or an aryl-C₁₋₃ alkyloxycarbonyl group, R⁷² is a hydrogenatom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group or an amino-C₂₋₃alkyl group,

R³¹ is a hydrogen atom, a halogen atom, a C₁₋₄ alkyl group or an arylgroup,

R⁴¹ is a C₆₋₁₀ alkyl group; a monocyclic group or a polycyclic groupconsisting of a 5- or 6-membered aromatic ring containing 0 to 3heteroatoms selected from N, O and S, which may optionally besubstituted by 1 to 3 atoms or groups selected from a halogen, a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a trifluoromethyl, a trifluoroethyl, an aryl,an aryl-C₁₋₃ alkyl, a C₁₋₃ alkoxy, a trifluoromethoxy, an aryloxy, aC₁₋₃ alkylcarbonyl, a C₃₋₇ cycloalkylcarbonyl, a nitro, a cyano, ahydroxy, a C₁₋₃ alkylthio, a C₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, acarboxy-C₁₋₃ alkyl, a C₁₋₄ alkoxycarbonyl and carboxyl; a C₅₋₇cycloalkenyl group which may optionally be substituted by 1 to 4 atomsor groups selected from a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, a fluorine, atrifluoromethyl, an aryl, a C₁₋₃ alkoxy and a hydroxy; a group of theformula (B′):

(R^(a′), R^(b′), R^(c′) and R^(d′) are the same or different and each isa hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorineatom, a trifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group or ahydroxy group, or when R^(a′) and R^(b′) attach to the same carbon atom,then these groups may combine to form an oxo group, or when R^(c′) andR^(d′) attach to the same carbon atom, then these groups may combinetogether with said carbon atom to form a spiro ring, or 2 or 3 groupsselected from R^(a′), R^(b′) and R^(c′) may combine to form a C₆₋₁₅polycycloalkyl group, and n′ is an integer of 1 to 5); or a group of theformula (C′):

(R^(e′) and R^(f′) are the same or different and each is a hydrogenatom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorine atom, atrifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group, or a hydroxygroup, or when R^(e′) and R^(f′) attach to the same carbon atom, thenthese groups may combine together with said carbon atom to form a spiroring, and Z is a carbon atom, an oxygen atom or a sulfur atom),

R⁵¹ is a hydrogen atom, a halogen atom, a C₁₋₃ alkyl group, atrifluoromethyl group, a C₁₋₃ alkoxy group, a trifluoromethoxy group oran aryl group.

Preferable compounds of the formula (Ia) are compounds of the formula(Ia), wherein R⁴¹ is a monocyclic group or a polycyclic group consistingof a 5- or 6-membered aromatic ring containing 0 to 3 heteroatomsselected from N, O and S, which may optionally be substituted by 1 to 3atoms or groups selected from a halogen, a C₁₋₆ alkyl, a C₃₋₇cycloalkyl, a trifluoromethyl, an aryl, an aryl-C₁₋₃ alkyl, a C₁₋₃alkoxy, a trifluoromethoxy, a cyano, a C₁₋₃ alkylthio, a C₁₋₄alkoxycarbonyl and a carboxyl; a C₅₋₇ cycloalkenyl group which mayoptionally be substituted by 1 to 4 atoms or groups selected from a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a fluorine, a trifluoromethyl, an aryl and aC₁₋₃ alkoxy; a group of the formula (B″):

(R^(a″), R^(b″), R^(c″) and R^(d″) are the same or different and each isa hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorineatom, a trifluoromethyl group, an aryl group, or a C₁₋₃ alkoxy group, orwhen R^(a″) and R^(b″) attach to the same carbon atom, then these groupmay combine to form an oxo group, or when R^(c″) and R^(d″) attach tothe same carbon atom, then these groups may combine together with saidcarbon atom to form a spiro ring, or 2 or 3 groups selected from R^(a″),R^(b″) and R^(c″) may combine to form a C₆₋₁₅ polycycloalkyl group, andn′ is an integer of 1 to 5); or a group of the following formula (C″):

(R^(e″) and R^(f″) are the same or different and each is a hydrogenatom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorine atom, atrifluoromethyl group, an aryl group or a C₁₋₃ alkoxy group, or whenR^(e″) and R^(f″) attach to the same carbon atom, then these groups maycombine together with said carbon atom to form a spiro ring, Z is acarbon atom, an oxygen atom, or a sulfur atom),

R¹¹, R²¹, R³¹, R⁵¹ are as defined above,

or a pharmaceutically acceptable salt thereof, or a hydrate or solventthereof.

More preferably compounds of the formula (Ia) are N-arylphenylacetamidederivatives of the formula (Ia) wherein R¹¹ is a methoxy group,

R²¹ is a hydrogen atom, an acetyl group, an ethylcarbonyl group, apropylcarbonyl group, an isopropylcarbonyl group, a butylcarbonyl group,a tert-butylcarbonyl group, a benzoyl group or a 2-aminoethyl group,

R³¹ is a hydrogen atom or a iodine atom,

R⁴¹ is a phenyl group, a naphthyl group, a thienyl group, a pyrrolylgroup, a benzo[d]-1,3-dioxolanyl group, a benzo[b]furanyl group, abenzo[b]thiophenyl group or a dibenzo[b,d]furanyl group, which mayoptionally be substituted by 1 to 3 atoms or groups selected from afluorine, a chlorine, a methyl, an ethyl, a propyl, an isopropyl, atert-butyl, a cyclopentyl, a cyclohexyl, a trifluoromethyl, a phenyl, afluorophenyl, a chlorophenyl, a methylphenyl, a trifluoromethylphenyl, atrifluoromethoxyphenyl, a trifluoromethoxy, a methylthio, amethoxycarbonyl, an ethoxycarbonyl, a tert-butoxycarbonyl and acarboxyl; or a cyclohexenyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group, a bicyclo[2,2,2]octyl group, an adamantylgroup, a 1-piperidinyl group, a 7-azaspiro[4,5]decan-7-yl group, a2-azaspiro[5,5]-undecan-2-yl group, a 1-azaspiro[5,5]undecan-1-yl group,a 4-morpholinyl group, a 4-thiomorpholinyl group or a1-oxa-4-azaspiro-[5,5]undecan-4-yl group, which may optionally besubstituted by 1 to 4 atoms or groups selected from a methyl, an ethyl,a propyl, an isopropyl, a tert-butyl, a cyclopentyl, a cyclohexyl, afluorine, a trifluoromethyl, a phenyl, a fluorophenyl, a chlorophenyl, amethylphenyl, a trifluoromethylphenyl and a trifluoromethoxyphenyl,

R⁵¹ is a hydrogen atom, a fluorine atom, a methyl group, atrifluoromethyl group, a methoxy group, a trifluoromethoxy group or aphenyl group,

or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.

N-arylphenylacetamide derivatives of the following formula (Ib),

or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof may also be included within the compounds of the above formula(I′).

wherein R¹¹ is a C₁₋₄ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group, a C₁₋₆ alkylsulfonylamino group, or anarylsulfonylamino group,

R²¹ is a hydrogen atom, a C₁₋₆ alkylcarbonyl group, an arylcarbonylgroup or —(CH₂)₂—N(R⁶²)(R⁷²), in which R⁶² is a hydrogen atom, a C₁₋₃alkyl group, a hydroxy-C₂₋₃ alkyl group, an amino-C₂₋₃ alkyl group, aformyl group, or an aryl-C₁₋₃ alkyloxycarbonyl group, and R⁷² is ahydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group or anamino-C₂₋₃ alkyl group,

R³¹ is a hydrogen atom, a halogen atom, a C₁₋₄ alkyl group or an arylgroup,

Y″ is —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CH═CH—, —C≡C—, —CO—, —COCH₂—,—CO(CH₂)₂—, —COCH═CH—, —O— or —O(CH₂)₂—,

R⁸¹ is a monocyclic group or a polycyclic group consisting of a 5- or6-membered aromatic ring containing 0 to 3 heteroatoms selected from N,O and S, which may optionally be substituted by 1 to 3 atoms or groupsselected from a halogen, a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, atrifluoromethyl, a trifluoroethyl, an aryl, an aryl-C₁₋₃ alkyl, a C₁₋₃alkoxy, a trifluoromethoxy, an aryloxy, a C₁₋₃ alkylcarbonyl, a C₃₋₇cycloalkylcarbonyl, a nitro, a cyano, a hydroxy, a C₁₋₃ alkylthio, aC₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, a carboxy-C₁₋₃ alkyl, a C₁₋₄alkoxycarbonyl and a carboxyl; a C₅₋₇ cycloalkenyl group which mayoptionally be substituted by 1 to 4 atoms or groups selected from a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a fluorine, a trifluoromethyl, an aryl, a C₁₋₃alkoxy and a hydroxy; or a group of the formula (B′):

(R^(a′), R^(b′), R^(c′) and R^(d′) are the same or different and each isa hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorineatom, a trifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group or ahydroxy group, or when R^(a′) and R^(b′) attach to the same carbon atom,then these groups may combine to form an oxo group, or when R^(c′) andR^(d′) attach to the same carbon atom, then these groups may combinetogether with said carbon atom to form a spiro ring, or 2 or 3 groupsselected from R^(a′), R^(b′) and R^(c′) may combine to form a C₆₋₁₅polycycloalkyl group, and n′ is an integer of 1 to 5),

R⁵¹ is a hydrogen atom, a halogen atom, a C₁₋₃ alkyl group, atrifluoromethyl group, a C₁₋₃ alkoxy group, a trifluoromethoxy group oran aryl group.

More preferable compounds of the formula (Ib) are compounds of theformula (Ib), wherein Y″ is —(CH₂)₂—, —CH═CH—, —C≡C—, —O— or —O(CH₂)₂—,R⁸¹ is a monocyclic group or a polycyclic group consisting of a 5- or6-membered aromatic ring containing 0 to 3 heteroatoms selected from N,O and S, which may optionally be substituted by 1 to 3 atoms or groupsselected from a halogen, a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, atrifluoromethyl, an aryl, an aryl-C₁₋₃ alkyl, a C₁₋₃ alkoxy, atrifluoromethoxy, a cyano, a C₁₋₃ alkylthio, a C₁₋₄ alkoxycarbonyl and acarboxyl; a C₅₋₇ cycloalkenyl group which may optionally be substitutedby 1 to 4 atoms or groups selected from a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl,a fluorine, a trifluoromethyl, an aryl and a C₁₋₃ alkoxy; or a group ofthe formula (B″):

(wherein R^(a″), R^(b″), R^(c″) and R^(d″) are the same or different andeach is a hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, afluorine atom, a trifluoromethyl group, an aryl group or a C₁₋₃ alkoxygroup, or when R^(a″) and R^(b″) attach to the same carbon atom, thenthese groups may combine to form an oxo group, or when R^(c″) and R^(d″)attach to the same carbon atom, then these groups may combine togetherwith said carbon atom to form a spiro ring, or 2 or 3 groups selectedfrom R^(a″), R^(b″) and R^(c″) may combine to form a C₆₋₁₅polycycloalkyl group, and n′ is an integer of 1 to 5), and R¹¹, R²¹,R³¹, R⁵¹ are as defined above,or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.

Further preferable compounds of the formula (Ib) areN-arylphenylacetamide derivatives of the formula (Ib), wherein R¹¹ is amethoxy group,

R²¹ is a hydrogen atom, an acetyl group, an ethylcarbonyl group, apropylcarbonyl group, an isopropylcarbonyl group, a butylcarbonyl group,a tert-butylcarbonyl group, a benzoyl group, a 2-aminoethyl group,

R³¹ is a hydrogen atom or a iodine atom,

Y″ is —(CH₂)₂—, —CH═CH—, —C≡C—, —O— or —O(CH₂)₂—,

R⁸¹ is a phenyl group, a naphthyl group or a thienyl group, which mayoptionally be substituted by 1 to 3 atoms or groups selected from afluorine, a chlorine, a methyl, an ethyl, a propyl, an isopropyl, atert-butyl, a cyclopentyl, a cyclohexyl, a trifluoromethyl, a phenyl, afluorophenyl, a chlorophenyl, a methylphenyl, a trifluoromethylphenyl, atrifluoromethoxyphenyl, a trifluoromethoxy, a methylthio and amethoxycarbonyl; or a cyclohexenyl group, a cyclopentyl group, acyclohexyl group, a cycloheptyl group, a bicyclo[2,2,2]octyl group or anadamantyl group, which may optionally be substituted by 1 to 4 atoms orgroups selected from a methyl, an ethyl, a propyl, an isopropyl, atert-butyl, a cyclopentyl, a cyclohexyl, a fluorine, a trifluoromethyl,a phenyl, a fluorophenyl, a chlorophenyl, a methylphenyl, atrifluoromethylphenyl and a trifluoromethoxyphenyl,

R⁵¹ is a hydrogen atom, a fluorine atom, a methyl group, atrifluoromethyl group, a methoxy group, a trifluoromethoxy group or aphenyl group,

or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.

N-arylphenylacetamide derivatives of the following formula (Ic) or apharmaceutically acceptable salt thereof, or a hydrate or solvatethereof may also be included within the compound of the formula (I′).

wherein R¹¹ is a C₁₋₄ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group, a C₁₋₆ alkylsulfonylamino group or anarylsulfonylamino group,

R²¹ is a hydrogen atom, a C₁₋₆ alkylcarbonyl group, an arylcarbonylgroup or —(CH₂)₂—N(R⁶²)(R⁷²), in which R⁶² is a hydrogen atom, a C₁₋₃alkyl group, a hydroxy-C₂₋₃ alkyl group, an amino-C₂₋₃ alkyl group, aformyl group or an aryl-C₁₋₃ alkyloxycarbonyl group, and R⁷² is ahydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group or anamino-C₂₋₃ alkyl group,

R³¹ is a hydrogen atom, a halogen atom, a C₁₋₄ alkyl group or an arylgroup,

R⁴² and R⁵² may combine together with the benzene ring to which theybond to form a group selected from the following group:

(R⁹¹ is a C₁₋₈ alkyl group; an aryl-C₁₋₃ alkyl group; a C₃₋₇cycloalkyl-C₁₋₃ alkyl group; or an arylsulfonyl group, R⁹² is a C₁₋₇alkyl group; a C₁₋₇ alkenyl group; a phenyl group which may optionallybe substituted by 1 to 3 atoms or groups selected from a halogen, a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a trifluoromethyl, a trifluoroethyl, an aryl,an aryl-C₁₋₃ alkyl, a C₁₋₃ alkoxy, a trifluoromethoxy, an aryloxy, aC₁₋₃ alkylcarbonyl, a C₃₋₇ cycloalkylcarbonyl, a nitro, a cyano, ahydroxy, a C₁₋₃ alkylthio, a C₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, acarboxy-C₁₋₃ alkyl, a C₁₋₄ alkoxycarbonyl and a carboxyl; an aryl-C₁₋₂alkyl group; a C₃₋₇ cycloalkyl group; or a C₃₋₇ cycloalkyl-C₁₋₂ alkylgroup).

More preferable compounds of the formula (Ic) are N-arylphenylacetamidederivatives of the formula (Ic), wherein R¹¹ is a methoxy group,

R²¹ is a hydrogen atom, an acetyl group, an ethylcarbonyl group, apropylcarbonyl group, an isopropylcarbonyl group, a butylcarbonyl group,a tert-butylcarbonyl group, a benzoyl group, a 2-aminoethyl group,

R³¹ is a hydrogen atom or a iodine atom,

R⁴² and R⁵² may combine together with the benzene ring to which theybond to form a group selected from the following group:

(R⁹³ is a butyl group, a pentyl group, a hexyl group, an isobutyl group,a heptyl group, or a benzyl group, a phenethyl group or a phenylpropylgroup, wherein the benzene ring moiety may optionally be substituted by1 to 3 atoms or groups selected from a fluorine, a chlorine, a methyl,an ethyl, a propyl, an isopropyl, a tert-butyl, a cyclohexyl, atrifluoromethyl, a phenyl, a fluorophenyl, a chlorophenyl, amethylphenyl, a trifluoromethylphenyl, a trifluoromethoxyphenyl, atrifluoromethoxy, a methylthio and a methoxycarbonyl, and R⁹⁴ is anisopropyl group, or a phenyl group which may optionally be substitutedby 1 to 3 atoms or groups selected from a fluorine, a chlorine, amethyl, an ethyl, a propyl, an isopropyl, a tert-butyl, a cyclohexyl, atrifluoromethyl, a phenyl, a fluorophenyl, a chlorophenyl, amethylphenyl, a trifluoromethylphenyl, a trifluoromethoxyphenyl, atrifluoromethoxy, a methylthio and a methoxycarbonyl),or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.

The compounds of the present invention may be grouped as follows,according to the characteristics of the chemical structure of thesubstituent R².

Compound of the formula (I) wherein R² is a hydrogen atom, and R¹, R³,R⁴, R⁵ and X¹ are as defined above, or a pharmaceutically acceptablesalt thereof, or a hydrate or solvate thereof;

Compound of the formula (I), wherein R² is a C₁₋₆ alkylcarbonyl group oran arylcarbonyl group, and R¹, R³, R⁴, R⁵ and X¹ are as defined above,or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof;

Compound of the formula (I) wherein R² is —(CH₂)_(m)—N(R⁶)(R⁷), and R¹,R³, R⁴, R⁵, m, R⁶, R⁷ and X¹ are as defined above, or a pharmaceuticallyacceptable salt thereof, or a hydrate or solvate thereof; and

Compound of the formula (I) wherein R² is —(CH₂)_(m)OH or—(CH₂)_(q)COOH, and R¹, R³, R⁴, R⁵, m, q and X¹ are as defined above, ora pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.

The N-arylphenylacetamide derivatives of the formulae (I′), (Ia), (Ib)and (Ic), or a pharmaceutically acceptable salt thereof, or a hydrate orsolvate thereof may also be grouped according to the aboveclassification.

Examples of the preferable compounds are the following compounds, or apharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.

-   N-(3-cyclohexylphenyl)-4-hydroxy-3-methoxyphenylacetamide (the    compound of Example 1),-   N-[3-(adamantan-2-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide (the    compound of Example 3),-   N-(3-cyclopentylphenyl)-4-hydroxy-3-methoxyphenylacetamide (the    compound of Example 4),-   N-[3-(cyclohexylmethyl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 5),-   N-[3-(cyclohexen-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 9),-   4-hydroxy-3-methoxy-N-[3-(2-phenylcyclohexan-1-yl)    phenyl]-phenylacetamide (the compound of Example 11),-   4-hydroxy-3-methoxy-N-[3-(4-methylcyclohexan-1-yl)phenyl]-phenylacetamide    (the compound of Example 13),-   N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 20),-   4-hydroxy-3-methoxy-N-(3-phenylphenyl)phenylacetamide (the compound    of Example 35),-   4-hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]phenylacetamide    (the compound of Example 36),-   4-hydroxy-3-methoxy-N-[3-(2-phenylethyl)phenyl]phenylacetamide (the    compound of Example 54),-   4-hydroxy-3-methoxy-N-[3-[(Z)-2-phenylvinyl]phenyl]phenylacetamide    (the compound of Example 56),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(2-phenylethyl)phenyl]-phenylacetamide    (the compound of Example 60),-   4-(2-aminoethoxy)-N-(3-cyclohexylphenyl)-3-methoxyphenylacetamide    (the compound of Example 61),-   4-(2-aminoethoxy)-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 62),-   4-(2-aminoethoxy)-3-methoxy-N-(3-phenylphenyl)phenylacetamide (the    compound of Example 63),-   4-(2-aminoethoxy)-N-[3-(3-fluorophenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 66),-   4-(2-aminoethoxy)-N-[3-(4-chlorophenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 67),-   4-acetoxy-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 69),-   4-benzoyloxy-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 70),-   4-tert-butylcarbonyloxy-N-[3-(4-tert-butylcyclohexan-1-yl)-phenyl]-3-methoxyphenylacetamide    (the compound of Example 71),-   N-[3-(4-tert-butylcyclohexen-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 80),-   4-hydroxy-3-methoxy-N-[3-(4-trifluoromethylcyclohexan-1-yl)-phenyl]phenylacetamide    (the compound of Example 81),-   4-hydroxy-3-methoxy-N-[3-(3-methylcyclohexan-1-yl)phenyl]-phenylacetamide    (the compound of Example 83),-   N-[3-(2,6-dimethylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 84),-   N-[3-(3,5-dimethylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 85),-   N-[3-(4-tert-butylpiperidin-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 86),-   N-[3-(3-cyclohexylpiperidin-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 87),-   N-[3-(3-methylpiperidin-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide    (the compound of Example 88),-   N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-5-iodo-3-methoxyphenylacetamide    (the compound of Example 98),-   4-hydroxy-3-methoxy-N-[3-(2-chlorothiophen-5-yl)phenyl]-phenylacetamide    (the compound of Example 100),-   4-hydroxy-3-methoxy-N-[3-(1-tert-butoxycarbonylpyrrol-2-yl)-phenyl]phenylacetamide    (the compound of Example 101),-   4-hydroxy-3-methoxy-N-[3-(2-cyclohexylethyl)phenyl]phenylacetamide    (the compound of Example 114),-   4-(2-aminoethoxy)-N-[3-(2-cyclohexylphenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 122),-   4-(2-aminoethoxy)-N-[3-(2-fluorophenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 123),-   4-(2-aminoethoxy)-N-[3-(4-fluorophenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 124),-   4-(2-aminoethoxy)-N-[3-(2-chlorophenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 125),-   4-(2-aminoethoxy)-N-[3-(3-chlorophenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 126),-   4-(2-aminoethoxy)-N-[3-(3,5-difluorophenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 129),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(2-methylphenyl)phenyl]-phenylacetamide    (the compound of Example 131),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(2,4,6-trimethylphenyl)-phenyl]phenylacetamide    (the compound of Example 133),-   4-(2-aminoethoxy)-N-[3-(3-isopropylphenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 136),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(4-trifluoromethylphenyl)-phenyl]phenylacetamide    (the compound of Example 140),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(2-trifluoromethylphenyl)-phenyl]phenylacetamide    (the compound of Example 142),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(2-phenylphenyl)phenyl]-phenylacetamide    (the compound of Example 143),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(3-phenylphenyl)phenyl]-phenylacetamide    (the compound of Example 145),-   4-(2-aminoethoxy)-N-[3-(3-methoxycarbonylphenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 146),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(3-trifluoromethoxyphenyl)-phenyl]phenylacetamide    (the compound of Example 150),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(2-methylthiophenyl)-phenyl]phenylacetamide    (the compound of Example 158),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(thiophen-3-yl)phenyl]-phenylacetamide    (the compound of Example 161),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(naphthalen-1-yl)phenyl]-phenylacetamide    (the compound of Example 163),-   4-(2-aminoethoxy)-N-[3-(2H-benzo[d]-1,3-dioxolan-5-yl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 164),-   4-(2-aminoethoxy)-N-[3-(benzofuran-2-yl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 166),-   4-(2-aminoethoxy)-N-[3-(3-tert-butylphenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 169),-   4-(2-aminoethoxy)-N-[(2-fluoro-5-phenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 170),-   4-(2-aminoethoxy)-N-[(2-methoxy-3-fluoro-5-phenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 171),-   4-(2-aminoethoxy)-N-[(2-methyl-5-phenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 172),-   4-(2-aminoethoxy)-3-methoxy-N-[(3-phenyl-4-methyl)phenyl]-phenylacetamide    (the compound of Example 173),-   4-(2-aminoethoxy)-3-methoxy-N-[(2-methoxy-5-phenyl)phenyl]-phenylacetamide    (the compound of Example 177),-   4-(2-aminoethoxy)-3-methoxy-N-[(3-trifluoromethyl-5-phenyl)-phenyl]phenylacetamide    (the compound of Example 178),-   4-(2-aminoethoxy)-3-methoxy-N-[(3-phenyl-4-trifluoromethoxy)-phenyl]phenylacetamide    (the compound of Example 179),-   4-(2-aminoethoxy)-3-methoxy-N-[(4-methyl-3,5-diphenyl)-phenyl]phenylacetamide    (the compound of Example 181),-   4-(2-aminoethoxy)-N-[3-(3-cyclohexylphenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 183),-   4-(2-aminoethoxy)-N-[3-(2-tert-butylphenyl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 184),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(3-phenoxyphenyl)phenyl]-phenylacetamide    (the compound of Example 186),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(2-phenylethyloxy)phenyl]-phenylacetamide    (the compound of Example 187),-   4-(2-aminoethoxy)-N-[3-[(cis)-4-tert-butylcyclohexan-1-yl]-phenyl]-3-methoxyphenylacetamide    (the compound of Example 194),-   4-(2-aminoethoxy)-N-[3-[(trans)-4-tert-butylcyclohexan-1-yl]-phenyl]-3-methoxyphenylacetamide    (the compound of Example 195),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(piperidin-1-yl)phenyl]-phenylacetamide    (the compound of Example 197),-   4-(2-aminoethoxy)-N-[3-(3-cyclohexylpiperidin-1-yl)phenyl]-3-methoxyphenylacetamide    (the compound of Example 199),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(3-phenylpiperidin-1-yl)-phenyl]phenylacetamide    (the compound of Example 200),-   4-(2-aminoethoxy)-3-methoxy-N-[3-(2-azaspiro[5,    5]undecan-2-yl)phenyl]phenylacetamide (the compound of Example 201),-   4-(2-aminoethoxy)-3-methoxy-N-[3-[2-(3-methylphenyl)ethyl]-phenyl]phenylacetamide    (the compound of Example 217),-   4-(2-aminoethoxy)-3-methoxy-N-[3-[2-(2-fluorophenyl)ethyl]-phenyl]phenylacetamide    (the compound of Example 219),-   4-(2-aminoethoxy)-3-methoxy-N-[1-oxo-2-phenylmethyl-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide    (the compound of Example 225),-   4-(2-aminoethoxy)-3-methoxy-N-[1-benzylindol-6-yl]phenylacetamide    (the compound of Example 238), and-   4-hydroxy-3-methoxy-N-[1-oxo-2-phenylmethyl-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide    (the compound of Example 249).

The compounds of the formula (I) include, for example, in addition tothe compounds of Examples as described below, the compounds of Table 1,and a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.

The following abbreviations may be used in the following Table 1,Reference Examples and Examples in order to simplify the description.

Me: methyl group, Et: ethyl group, i-Pr: isopropyl group, Bu: butylgroup, t-Bu: tert-butyl group, Ph: phenyl group, Ms: methanesulfonylgroup, Boc: tert-butoxycarbonyl group.

TABLE 1

R¹ R² R³ R⁴ R⁵ MeO H₂NCH₂CH₂— H

H HO H 6-I

4-CF₃ MsNH H₂NCH₂CH₂— H

H MeO H 5-I

H MeO H₂NCH₂CH₂— 2-I —Ph 4-F Cl H₂NCH₂CH₂— H —CH₂CH₂Ph H PhSO₂NHH₂NCH₂CH₂— H —Ph H MeO HOCH₂CH₂HNCH₂CH₂— H —Ph 3-OCF₃ MeO(HOCH₂CH₂)₂NCH₂CH₂— H

H MeO H₂NCH₂CH₂HNCH₂CH₂— 5-Br

H MeO HOOCCH₂CH₂— 5-Cl

H NO₂ H₂NCH₂CH₂— H

2-Me MeO H₂NCH₂CH₂— H

H MeO H₂NCH₂CH₂— 5-Bu-t

H NH₂ H H

H MeO H₂NCH₂CH₂— 5-CHO

H Me₂N H H

H MeO PhCO— H

H MeO H₂NCH₂CH₂— H

4-Cl

The compounds of the formula (I) may be prepared, for example, by thefollowing Processes.

Process A

The compound of the formula (I) wherein R² is a-hydrogen atom, a C₁₋₆alkylcarbonyl group, an arylcarbonyl group or —(CH₂)_(m)—N(R⁶)(R⁷) [m,R⁶ and R⁷ are as defined above, except that —N(R⁶)(R⁷) is a primary orsecondary amino group] may be prepared by reacting a compound of theformula (IIa):

wherein R²² is a hydrogen atom, a C₁₋₆ alkylcarbonyl group, anarylcarbonyl group or —(CH₂)_(m)—N(R⁶)(R⁷) [m, R⁶ and R⁷ are as definedabove, excluding the compound wherein —N(R⁶)(R⁷) is a primary orsecondary amino group], R¹ and R³ are as defined above, with a compoundof the formula (III):

wherein R⁴, R⁵ and X¹ are as defined above.

The reaction of the compound of the formula (IIa) and the compound ofthe formula (III) is carried out under conventional reaction conditionsfor amide bond forming reaction. The compound of the formula (IIa) maybe reacted with the compound of the formula (III) after it is convertedinto a reactive derivative at the carboxyl group thereof.

The reactive derivative of a carboxyl group of the compound of theformula (IIa) is, for example, a lower alkyl ester (especially, methylester), an active ester, an acid anhydride, an acid halide (especiallyan acid chloride). The active ester is, for example, p-nitrophenylester, N-hydroxysuccinimide ester, pentafluorophenyl ester. The acidanhydride is, for example, a symmetric acid anhydride or a mixed acidanhydride with ethyl chlorocarbonate, isobutyl chlorocarbonate,isovaleric acid, pivalic acid, etc.

When the compound of the formula (IIa) per se is used, the presentreaction is usually carried out in the presence of a condensing agent.The condensing agent is, for example, N,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,N,N′-carbonyldiimidazole,benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate,etc. These condensing agents are used alone, or in a combination ofthese condensing agents and a peptide synthesis reagent such asN-hydroxysuccinimide, N-hydroxybenzotriazole, etc.

The reaction of the compound of the formula (IIa) or a reactivederivative thereof with the compound of the formula (III) is carried outin a solvent or without a solvent. The solvent used should be selectedaccording to the kinds of the starting compound, etc., and includes, forexample, toluene, tetrahydrofuran, dioxane, ethylene glycol dimethylether, methylene chloride, chloroform, ethyl acetate, acetone,acetonitrile, dimethylformamide, etc. These solvents may be used aloneor in the form of a mixture of two or more solvents. The compound of theformula (III) may be used in the form of an acid addition salt such ashydrochloride, etc., to produce a free basic compound in the reactionsystem.

This reaction is usually carried out in the presence of a base. The baseincludes, for example, an inorganic base such as potassium carbonate,sodium hydrogen carbonate, or an organic base such as triethylamine,ethyldiisopropylamine, N-methylmorpholine, pyridine,4-dimethylaminopyridine, etc. The reaction temperature may varyaccording to the kinds of the starting compounds used, and it is usuallyin the range of about −30° C. to about 150° C., preferably in the rangeof about −10° C. to about 70° C. When the compound (IIa) or the compound(III) has a functional group participating in the reaction within thestructure thereof, it is preferable to protect such functional groups bya conventional method, and to remove the protecting groups after thereaction is complete.

The starting compound (IIa) of this reaction may be commerciallyavailable ones or may be prepared by a conventional method, such asmethods disclosed in Korean J. Med. Chem., 1, 36 (1991); J. Med. Chem.,39, 4942 (1996); J. Chem. Soc. Perkin Trans. 1, 833 (1984); J. Am. Chem.Soc., 72, 5163 (1950); J. Org. Chem., 24, 4658 (1983) and Synthesis, 126(1981), or a modified method of these methods.

On the other hand, the compound of the formula (III) may be commerciallyavailable ones or may be prepared by the following Process.

wherein A is a leaving atom or a leaving group, and R⁴, R⁵ and X¹ are asdefined above.

The leaving atom or leaving group for A in the formula (IV) is, forexample, a halogen atom, a trifluoromethanesulfonyloxy group, a hydroxygroup, and a boronic acid group.

(Step 1)

When R⁴ of the compound of the formula (V) is a C₆₋₁₀ alkyl group, or agroup of the above formula (A) [in which Y is a single bond, a C₁₋₃alkylene group, a C₂₋₃ alkenylene group, a C₂₋₃ alkynylene group or aC₂₋₃ alkenylenecarbonyl group, and R⁸ is as defined above], for example,when A of the compound of the formula (IV) is a halogen atom or atrifluoromethanesulfonyloxy group, Step 1 is carried out using an organozinc derivative, an organo tin derivative, an arylboronic acidderivative, an alkyne derivative, an alkene derivative, etc., and whenthe compound of the formula (IV) is an organo zinc derivative, an organotin derivative, an arylboronic acid derivative, an alkyne derivative oran alkene derivative, then Step 1 is carried out using a halogenderivative, a trifluoromethanesulfonyloxy derivative, etc., by themethod disclosed in J. Org. Chem., 56, 1445 (1991); Angew. Chem. Int.Ed. Engl., 25, 508 (1986); Synth. Commun., 11, 513 (1981); Synthesis,627 (1980); Org. React., 27, 345 (1982) or Synthesis, 993 (1991), or bya modified method thereof.

The compound of the formula (V) wherein R⁴ is a group of the aboveformula (A) (in which Y is —CO(CH₂)_(p)— or —CONH(CH₂)_(p)— and R⁸ is asdefined above) may be commercially available ones or prepared by aconventional method or a modified method thereof.

In the case of the compound of the formula (V) wherein R⁴ is a group ofthe formula (A) (in which Y is —O—, —O—(CH₂)₂— or —O—(CH₂)₃— and R⁸ isas defined above), for example, when the starting compound of theformula (IV) wherein A is a halogen atom, and a phenol derivative areused, the reaction is carried out by the method disclosed in Chem. Ber.,38, 2212 (1905) or J. Org. Chem., 50, 3717 (1985), or when the staringcompound of the formula (IV) wherein A is a hydroxy group and a halogenderivative or an alcohol compound are used, the reaction is carried outby the method disclosed in J. Med. Chem., 25, 57 (1982); J. Pharm. Sci.,56, 871 (1967) or Org. React., 42, 335 (1992), or a modified methodthereof.

In the case of the compound of the formula (V) wherein R⁴ is a group ofthe above formula (C), for example, when the starting compound of theformula (IV) wherein A is a trifluoromethanesulfonyloxy group or ahalogen atom, and an amine derivative are used, Step 1 is carried out,for example, by the method disclosed in Tetrahedron Lett., 39, 7979(1998) or Tetrahedron, 55, 13285 (1999), or a modified method thereof.

(Step 2)

This Step is carried out by treating the compound of the formula (V) ina suitable solvent with a reducing agent suitable for reduction of anitro group into an amino group, or by catalytic reduction. The reducingagent is, for example, a combination of a metal (e.g., iron, zinc, tin,etc.) or a metal salt (e.g., stannic chloride, etc.) and an acid or asalt thereof (e.g., hydrochloric acid, acetic acid, ammonium acetate,etc.). Stannic chloride may be used alone. The catalytic reduction iscarried out in the presence of a catalyst (e.g., palladium on carbon,platinum, etc.) under atmospheric pressure or under pressure. Thesolvent used should be selected according to the kinds of the reducingagent or catalyst, etc., and includes, for example, ethanol, ethylacetate, acetone, dimethylformamide, water, acetic acid, hydrochloricacid, etc., and these solvents may be used alone, or in the form of amixture of two or more of these solvents. The reaction temperature mayvary according to the kinds of the reducing agents or catalysts to beused, etc. and it is usually in the range of 20° C. to 150° C.

The compound of the formula (III) wherein R⁴ and R⁵ combine togetherwith the benzene ring to which they bond, and form a tetralone ring oran indole ring may be prepared by aldole reaction or alkylation reactionin the presence of a base of a commercially available tetralone orindole derivative, followed by treating in a similar manner to the above(Step 2). Examples of this reaction are shown in Reference Example 8 andReference Example 9.

Process B

The compound of the formula (I) wherein R² is —(CH₂)_(m)OH or—(CH₂)_(q)COOH may be prepared by hydrolysis, acid decomposition orcatalytic hydrogenation of a compound of the formula (Id):

wherein R²³ is —(CH₂)_(m)OW¹ or —(CH₂)_(q)COOW¹, W¹ is a C₁₋₆ alkylgroup which may optionally be substituted by a methoxy group or anethoxy group, a benzyl group which may optionally be substituted by 1 or2 methoxy groups, and R¹, R³, R⁴, R⁵, X¹, m and q are as defined above.

Examples of W¹ of the above formula (Id) is a methyl group, an ethylgroup, a tert-butyl group, a methoxymethyl group, a 2-ethoxyethyl group,a benzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group.The hydrolysis is carried out by a conventional method, for example, byreacting with an alkali hydroxide such as sodium hydroxide, potassiumhydroxide in a suitable solvent. The solvent used is, for example,methanol, ethanol, tetrahydrofuran, water, and these solvents may beused alone, or in the form of a mixture of two or more solvents.

The acid decomposition is carried out, for example, by treating with aLewis acid (e.g., trimethylsilyl trifluoromethanesulfonic acid ester,boron trifluoride diethyl ether complex), an organic acid (e.g.,trifluoroacetic acid, trifluoromethanesulfonic acid, etc.), an inorganicacid (e.g., hydrochloric acid, etc.). The solvent used is, for example,diethyl ether, methylene chloride, ethyl acetate, methanol, ethanol,tetrahydrofuran, water, and these solvents may be used alone, or in theform of a mixture of two or more solvents.

The catalytic hydrogenation is carried out in a conventional manner, forexample, using palladium on carbon, palladium hydroxide, platinum as acatalyst. The solvent used is, for example, ethyl acetate, methanol,ethanol, tetrahydrofuran, water, and these solvents may be used alone,or in the form of a mixture of two or more solvents.

In addition, said reaction may be carried out by a novel method, andsaid method should not be defined or limited.

The compound of the above formula (Id) may be prepared by reacting acompound of the formula (IIb):

wherein R¹, R²³ and R³ are as defined above,with the compound of the above formula (III) by a similar methoddisclosed in the above Process A.

The starting compound (IIb) may be commercially available ones or may beprepared by a conventional method, for example, it can be prepared by asimilar method to the method for preparing the starting compound (IIa)in the above Process A or by a modified method thereof.

Process C

The compound of the formula (I) wherein R² is —(CH₂)_(m)—NH(R⁶) may beprepared by the hydrolysis, acid decomposition or catalytichydrogenation as disclosed in Process B, or by reduction, catalytichydrogenation or hydrolysis as mentioned below of a compound of theformula (Ie):

wherein R²⁴ is —(CH₂)_(m)—N(R⁶)(W²), —(CH₂)_(m)—N₃ or —(CH₂)_(m)W³, W²is a C₁₋₆ alkyloxycarbonyl group, an aryloxycarbonyl group, an aryl-C₁₋₃alkyloxycarbonyl group, a C₁₋₆ alkylcarbonyl group or an arylcarbonylgroup, W³ is a cyclic imide group binding onto the nitrogen atom, andR¹, R³, R⁴, R⁵, R⁶, X¹ and m are as defined above. Examples of W² of theabove formula (Ie) are tert-butyloxycarbonyl group,9-fluorenyloxy-carbonyl group, benzyloxycarbonyl group. Example of W³ isphthalimid-1-yl group.

The compound of the formula (Ie) wherein R²⁴ is —(CH₂)_(m)—N₃ may beconverted into the compound of the formula (I) by treating with areducing agent suitable for reduction of an azide group into an aminogroup such as triphenylphosphine, or by catalytic hydrogenation. Thecatalytic hydrogenation is carried out in a conventional manner, forexample, using palladium on carbon, palladium hydroxide, platinum, as acatalyst. The solvent used is, for example, ethyl acetate, methanol,ethanol, tetrahydrofuran, water, and these solvents may be used alone,or in the form of a mixture of two or more solvents.

The compound of the formula (Ie) wherein R²⁴ is —(CH₂)_(m)W³ may beconverted into the compound of the formula (I) by a method suitable forconversion of a cyclic imide group into an amino group, for example, bytreating with hydrazine, an acid or a base. The acid used is, forexample, hydrochloric acid, sulfuric acid, etc., and the base used is,for example, sodium hydroxide, potassium hydroxide, etc. The solventused is, for example, ethyl acetate, methanol, ethanol, tetrahydrofuran,water, and these solvents may be used alone, or in the form of a mixtureof two or more solvents.

The compound of the above formula (Ie) may be prepared by reacting acompound of the formula (IIc):

wherein R¹, R²⁴ and R³ are as defined above,with the compound of the formula (III) in a similar manner to the aboveProcess A.

The starting compound (IIc) may be commercially available ones, or maybe prepared by a conventional method, for example, by the methoddisclosed in J. Med. Chem., 39, 2939 (1996), or the method for preparingthe starting compound (IIa) in the above Process A, or a modified methodthereof.

Process D

The compound of the formula (I) may be prepared by the reactiondisclosed in Step 1 of the above Process A using as a starting compounda compound of the formula (If):

wherein R¹, R², R³, R⁵, X¹ and A are as defined above.

The starting compound (If) of this reaction may be prepared in a similarmanner to the method disclosed in the above Process A, Process B andProcess C.

Process E

The compound of the formula (I) may be prepared by a conventionalmethod, for example, by the methods disclosed in WO 00/50387 andJP-A-63-295537, or a modified method thereof, using as a startingcompound a compound of the formula (Ig):

wherein R¹, R³, R⁴, X¹ and R⁵ are as defined above.

Examples of this Process are shown in Examples 33, 69, 70, 71, 72, 73,74, 119 and 206.

The compounds of the formula (I) obtained by the above Processes can beisolated and purified by a conventional method such as chromatography,recrystallization, re-precipitation, etc. The compound of the formula(I) can be obtained either in the form of a free base or an acidaddition salt thereof, according to the kinds of functional groupswithin the structure, the selection of the starting compounds, andreaction conditions, and these salts can be converted into the compoundof the formula (I) by a conventional method. On the other hand, thecompound of the formula (I) having a group being capable of forming anacid addition salt within the structure thereof may be converted into anacid addition salt thereof by treating with various acids in aconventional manner.

The pharmacological activities of the present compounds are explained bythe following pharmacological experiments on the representativecompounds of the present invention, but the present invention should notbe construed to be limited to these pharmacological experiments.

Experiment 1: Phenyl-1,4-benzoquinone-induced Writhing Test

Referring to the method disclosed in Proc. Soc. exp. Biol. Med., 95, 729(1957), the effect of the test compounds on the writhing test induced byphenyl-1,4-benzoquinone (Wako Pure Chemical Industries, Ltd., Japan)(hereinafter, referred to as PBQ) was examined using male Std:ddY micefasted overnight (five mice per group, body weight: 15 to 20 g). Forsubcutaneous administration, a test compound was dissolved in aphysiological saline solution containing 10% Tween 80 (Sigma, USA) and10% ethanol to give a suitable concentration. For oral administration, atest compound was suspended in 0.5% tragacanth solution. A test compoundwas administered 60 minutes before the intraperitoneal injection of PBQsolution (0.02% in physiological saline solution containing 5% ethanol),and the number of writhing movements for each mouse was counted for 10minutes from 5 minutes after the injection of PBQ. In the control group,a physiological saline solution containing 10% Tween 80 and 10% ethanolwas administered in the case of subcutaneous administration, or a 0.5%tragacanth solution was administered in the case of oral administration.The number of writhing movements in the test compound-treated group wascompared with that in the control group, and the writhing inhibitorypercentage was calculated therefrom and considered as an analgesiceffect.Writhing inhibitory percentage (%)=[(A−B)/A]×100

In the above equation, A means the number of writhing movements in thecontrol group, and B means the number of writhing movements in the testcompound-treated group. From the writhing inhibitory percentage of thetest compound, ED₅₀ (mg/kg) was calculated by logit analysis. The testresults are shown in Table 2, Table 3, Table 4 and Table 5.

TABLE 2 Inhibitory Test percentage Comp. (%)* Ex. 1 100 Ex. 3 91.3 Ex. 479.6 Ex. 5 83.5 Ex. 6 68.9 Ex. 9 93.2 Ex. 11 88.4 Ex. 12 78.7 Ex. 13 100Ex. 15 72.8 Ex. 16 64.1 Ex. 17 68.3 Ex. 20 96.1 Ex. 21 45.2 Ex. 24 47.1Ex. 34 41.5 Ex. 35 89.4 Ex. 36 92.3 Ex. 37 59.6 Ex. 45 58.3 Ex. 48 48.6Ex. 51 57.7 Ex. 52 47.6 Ex. 54 90.4 Ex. 56 82.7 Ex. 58 54.4 Ex. 59 61.0Ex. 60 50.5 Ex. 61 72.8 Ex. 62 100 Ex. 63 100 Ex. 64 56.1 Ex. 69 99.0Ex. 70 93.2 Ex. 71 94.2 Ex. 77 100 Ex. 78 94.5 Ex. 80 100 Ex. 81 100 Ex.82 66.7 Ex. 83 83.0 Ex. 84 67.7 Ex. 85 76.9 Ex. 86 78.8 Ex. 87 95.8 Ex.88 76.6 Ex. 93 65.3 Ex. 95 62.2 Ex. 96 47.0 Ex. 97 54.9 Ex. 100 100 Ex.101 100 Ex. 102 58.1 Ex. 114 98.0 Ex. 160 47.4 Ex. 167 55.2 Ex. 189 65.9Ex. 210 40.5 Ex. 233 67.0 Ex. 238 70.2 Ex. 243 62.2 Ex. 245 55.4 Ex. 24759.2 Ex. 249 89.4 Ex. 250 55.0 Ex. 251 42.7 Ex. 253 48.3 Ex. 254 42.5Ex. 255 64.9 Capsaicin 46.6 *Inhibitory percentage (%) when a testcompound was subcutaneously administered at a dose of 1 mg/kg.

TABLE 3 Test ED₅₀ Comp. (mg/kg sc) Ex. 1 0.014 Ex. 3 0.46 Ex. 5 0.57 Ex.9 0.23 Ex. 11 0.19 Ex. 12 0.32 Ex. 13 0.097 Ex. 17 0.62 Ex. 20 0.056 Ex.34 0.48 Ex. 35 0.23 Ex. 36 0.046 Ex. 37 0.46 Ex. 45 0.55 Ex. 51 0.74 Ex.54 0.081 Ex. 56 0.11 Ex. 59 0.53 Ex. 60 0.83 Ex. 61 0.13 Ex. 62 0.23 Ex.63 0.016 Ex. 69 0.088 Ex. 70 0.16 Ex. 71 0.16 Ex. 77 0.25 Ex. 78 0.13Ex. 80 0.37 Ex. 83 0.10 Ex. 84 0.45 Ex. 85 0.31 Ex. 86 0.33 Ex. 87 0.40Ex. 101 0.23 Ex. 233 0.55 Ex. 238 0.37 Ex. 249 0.043 Capsaicin 1.15

TABLE 4 Inhibitory Test percentage Comp. (%)* Ex. 20 97.1 Ex. 59 75.5Ex. 61 89.0 Ex. 62 96.1 Ex. 63 100 Ex. 66 100 Ex. 67 90.2 Ex. 69 73.5Ex. 70 68.6 Ex. 122 99.0 Ex. 123 100 Ex. 124 100 Ex. 125 93.0 Ex. 12689.9 Ex. 129 76.9 Ex. 131 100 Ex. 133 94.0 Ex. 136 99.0 Ex. 140 91.0 Ex.142 98.9 Ex. 143 73.2 Ex. 145 85.9 Ex. 146 76.9 Ex. 150 100 Ex. 158 95.1Ex. 161 79.4 Ex. 163 87.9 Ex. 164 99.0 Ex. 166 96.0 Ex. 169 100 Ex. 17087.9 Ex. 171 94.0 Ex. 172 75.9 Ex. 173 100 Ex. 177 78.9 Ex. 178 100 Ex.179 100 Ex. 181 80.9 Ex. 183 83.5 Ex. 184 100 Ex. 186 84.3 Ex. 194 96.2Ex. 195 77.7 Ex. 197 89.1 Ex. 199 71.6 Ex. 200 84.2 Ex. 201 100 Ex. 20973.0 Ex. 217 96.3 Ex. 218 74.0 Ex. 219 94.0 Ex. 225 73.5 Capsaicin20.6** *Inhibitory percentage (%) when a test compound was orallyadministered at a dose of 10 mg/kg. **Inhibitory percentage (%) whenCapsaicin was orally administered at a dose of 30 mg/kg.

TABLE 5 Test ED₅₀ Comp. (mg/kg po) Ex. 20 1.28 Ex. 59 0.93 Ex. 60 0.68Ex. 61 3.00 Ex. 62 0.43 Ex. 63 0.021 Ex. 69 2.81 Ex. 70 9.70 Ex. 1220.58 Ex. 123 0.76 Ex. 124 0.71 Ex. 125 0.71 Ex. 126 2.19 Ex. 129 1.89Ex. 131 1.10 Ex. 133 1.28 Ex. 136 3.11 Ex. 140 2.18 Ex. 142 1.19 Ex. 1433.72 Ex. 146 2.68 Ex. 150 1.32 Ex. 158 2.12 Ex. 161 2.79 Ex. 163 1.61Ex. 164 1.56 Ex. 166 2.40 Ex. 169 1.29 Ex. 170 1.06 Ex. 171 0.96 Ex. 1724.42 Ex. 173 0.87 Ex. 177 3.41 Ex. 178 1.65 Ex. 179 0.95 Ex. 181 1.11Ex. 183 3.09 Ex. 184 0.60 Ex. 186 1.83 Ex. 194 1.05 Ex. 197 5.26 Ex. 2012.04 Ex. 209 6.79 Ex. 217 1.13 Ex. 218 1.82 Ex. 219 1.46 Ex. 225 4.79Capsaicin >30

As shown in Table 2, the compounds of the present invention exhibited apotent analgesic activity by subcutaneous administration. The compoundsof Examples as shown in Table 3 showed a potent analgesic activity withan ED₅₀ of not more than 1 mg/kg (subcutaneous administration), andamong them, the compounds of Examples 1, 13, 20, 36, 54, 63, 69, 83 and249 especially showed an extremely potent analgesic activity with anED₅₀ of not more than 0.1 mg/kg (subcutaneous administration).

The compounds of the present invention as shown in Table 4 showed acomparatively potent analgesic activity by oral administration.Especially, the compounds of Examples 59, 60, 62, 63, 122, 123, 124,125, 171, 173, 179 and 184 showed a potent analgesic activity with anED₅₀ of not more than 1 mg/kg (oral administration).

Experiment 2: Study of Pungency (Eye Wiping Test)

The pungency of the test compounds were studied referring to the methodof Jancso et al. [Acta Physiol. Acad. Sci. Hung., 19, 113–131 (1961)]and the method of Szallasi et al. [Brit. J. Pharmacol., 119, 283–290(1996)]. A test compound was dissolved in a physiological salinesolution containing 10% ethanol and 10% Tween 80 into variousconcentrations (μg/ml), and a drop of the solution thereof was addeddropwise into the eye of Jcl:SD strain male rats (5 to 25 mice pergroup, body weight; 220 to 280 g). Then, the number of the protectivewiping movements with forefoot was counted for 3 minutes, and wasconsidered as an index for pungency. The test results are expressed asaverage value±S.E.M., and the statistical significant differencesbetween each test compound-treated group and the control group wereanalyzed using non-parametric Dunnett's multiple range test, and p<0.05was considered as significant difference. The results are shown in Table6.

TABLE 6 Number of Concentration wiping Test Comp. (μg/ml) movementsVehicle- — 2.0 ± 0.4 Control group Capsaicin 1 6.0 ± 0.8 2 7.8 ± 1.4 511.2 ± 3.0* 10  26.4 ± 6.0*** 20  38.0 ± 4.8*** Vehicle- — 3.2 ± 1.2Control group Ex. 61 20 2.0 ± 0.8 100 7.4 ± 2.1 500 15.6 ± 4.5* Vehicle-— 3.2 ± 1.1 Control group Ex. 60 500 4.2 ± 1.2 1000 8.4 ± 2.1 Ex. 62 5004.6 ± 1.2 1000 7.6 ± 1.4 Vehicle- — 1.2 ± 0.4 Control group Ex. 63 507.2 ± 1.2 200  12.8 ± 1.7** Vehicle- — 2.0 ± 1.1 Control group Ex. 20100 5.0 ± 1.3 500  10.6 ± 0.7** Ex. 66 100 5.6 ± 2.4 500 3.6 ± 1.6 Ex.67 100 3.8 ± 1.3 500  13.4 ± 2.8** Ex. 164 100 5.4 ± 2.8 500 2.8 ± 1.7Ex. 186 100 4.0 ± 1.1 500  12.2 ± 2.0** Vehicle- — 2.2 ± 1.1 Controlgroup Ex. 225 500 4.4 ± 2.1 1000 1.6 ± 1.2 *p < 0.05, **p < 0.01, ***p <0.001 (in comparison with the corresponding vehicle control group)

As is shown in Table 6, capsaicin significantly increased the number ofwiping movements at a dose of 5 μg/ml. On the other hand, the pungencyof each compound of Examples as listed in Table 6 was one-tenth or lessweaker than that of capsaicin. Among them, the compounds of Examples 60,62, 66, 164 and 225 showed no significant increase in the number ofwiping movements even at a high dose of 500 μg/ml, and their pungency isquiet weak.

As is apparent from the above test results, the compounds of the presentinvention, a pharmaceutically acceptable salt thereof, and a hydrate orsolvate thereof exhibit a potent analgesic effect with a weak pungency,and they are efficacious even in oral administration. Therefore, thecompounds of the present invention are useful as analgesic agents andantiinflammatory agents, and as an agent for treatment of neuropathicpain to which conventional analgesic agents are ineffective, or paincaused by rheumatic arthritis. In addition, the compounds of the presentinvention are also useful as a preventive and/or an agent for treatmentof essential pruritus, allergy or nonallergic rhinitis, frequenturination and urinary incontinence with overactive bladder, stroke,irritable bowel syndrome, respiratory disorders such as asthma andchronic obstructive pulmonary disease, dermatitis, mucositis, gastricand duodenal ulcer, inflammatory bowel diseases and obesity.

The compounds of the present invention can be administered eitherorally, parenterally, percutaneouslly, rectally or intravaginally, butoral administration, injection and percutaneous administration are morepreferable. The dose of the compounds of the present invention may varyaccording to the kinds of the compound, the administration routes, theconditions, ages of the patients, etc., but it is usually in the rangeof 0.01–150 mg/kg/day, preferably in the range of 0.1–20 mg/kg/day,which can be administered once a day or divided into several dosageforms.

The compounds of the present invention are usually administered in theform of a pharmaceutical preparation, which is prepared by mixingthereof with a pharmaceutically acceptable carrier or diluent. Thepharmaceutical preparation is, for example, oral preparations such astablets, capsules, granules, powders, syrups, etc., externalpreparations such as inhalants, nasal drops, ointments, patches,powders, etc., injection preparations such as intravenous injections,intramuscular injections, etc., drip infusions, eye-drops,suppositories, etc. These pharmaceutical formulations may be prepared bya conventional method.

The pharmaceutically acceptable carrier or diluent may be anyconventional ones usually used in the pharmaceutical field, and does notreact with the compounds of the present invention. Suitable examples ofthe pharmaceutically acceptable carrier or diluent for preparingtablets, capsules, granules and powders are, for example, excipientssuch as lactose, corn starch, white sugar, mannitol, calcium sulfate,crystalline cellulose, etc., disintegrants such as carmellose sodium,pregelatinized starch, carmellose calcium, etc., binders such asmethylcellulose, gelatin, gum arabic, ethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc., lubricants such as lightanhydrous silicic acid, magnesium stearate, talc, hydrogenated oil, etc.Tablets may be coated in a conventional manner with a coating agent suchas carnauba wax, hydroxypropylmethylcellulose, macrogol,hydroxypropylmethyl phthalate, cellulose acetate phthalate, white sugar,titanium oxide, sorbitan fatty acid esters, calcium phosphate, etc.

Suitable examples of the pharmaceutically acceptable carrier or diluentfor preparing syrups are sweetening agents such as white sugar, glucose,fructose, etc., suspending agents such as gum arabic, tragacanth,carmellose sodium, methylcellulose, sodium alginate, crystallinecellulose, bee gum, etc., dispersing agents such as sorbitan fatty acidester, sodium lauryl sulfate, polysorbate 80, etc. If necessary,corrigents, flavors, preservatives may be added to syrups. Syrups may bein the form of a dry syrup, which is dissolved or suspended when used.

Suitable examples of the base for ointments are white petrolatum,plastivase, bleached beeswax, purified lanolin, hydrogenated caster oil,macrogol. When preparing ointments, if necessary, vegetable oils, liquidparaffin, etc. may be added thereto.

Suitable examples of the adhesive base for patches are polymer basessuch as polyvinylpyrrolidone, polyisobutylene, vinyl acetate copolymer,acrylic copolymer, etc., plasticizers such as glycerin, propyleneglycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate,diethyl phthalate, diethyl sebacate, dibutyl sebacate, acetylatedmonoglyceride, etc.

Suitable examples of the base for suppositories are cacao butter,saturated fatty acid glycerin ester, glycerogelatin, macrogol. whenpreparing suppositories, if necessary, surfactants, preservatives may beadded to suppositories.

Injection preparations may be prepared by dissolving an acid additionsalt of the compound (I) in a distilled water for injection, but ifnecessary, there may be added solubilizing agents, buffering agents, pHadjusters, isotonic agents, soothing agents, preservatives. Moreover,injection preparations may be in the form of a suspension, which isprepared by suspending the compound of the present invention per se indistilled water for injection or a vegetable oil. In these cases, ifnecessary, bases, suspending agents, thickening agents may be addedthereto. Further, injection preparations may be in the form of powder ormay be lyophilized, and it is dissolved when used, and in these cases,if necessary, excipients, etc. may be added thereto.

The content of the compound of the present invention in pharmaceuticalcompositions may vary based on the dosage forms, and it is usually inthe range of 0.01 to 70% by weight to the total weight of thepharmaceutical composition. These pharmaceutical compositions may alsocontain other therapeutically effective compounds as well.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be illustrated in more detail by ReferenceExamples and Examples, but it should not be construed to be limitedthereto. The compounds were identified by Elementary Analysis, Massspectrum, IR spectrum, NMR spectrum, HPLC, etc.

The conditions for HPLC are as follows:

Column: CAPCELL PAK C18 SG 120 (manufactured by Shiseido Co., Ltd.), φ4.6×150 mm,

Temperature: 25° C.,

Flow: 1 ml/min.,

Solvent for elution: 10%, 20%, 25%, 30%, 40%, 45%, 50%, 65% or 75%acetonitrile/0.05% aqueous trifluoroacetic acid solution (concentrationfor each Example is shown in Table 36), UV (254 nm).

REFERENCE EXAMPLE 1 Preparation of4-hydroxy-N-(3-iodophenyl)-3-methoxyphenylacetamide (Intermediate 1)

A mixture of 4-hydroxy-3-methoxyphenylacetic acid (4.65 g),pentafluorophenol (4.2 g),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.9 g) andmethylene chloride (50 ml) was stirred at room temperature for 18 hours.The reaction solution was washed with water, and the organic layer wasdried over sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: gradient from 0% to 100% hexane/ethyl acetate) to give4-hydroxy-3-methoxyphenylacetic acid pentafluorophenyl ester (7.8 g).This product is dissolved in ethyl acetate (80 ml), and thereto is added3-iodeaniline (7.4 g). The mixture is heated at 60° C. under stirringfor 18 hours. The solvent is evaporated under reduced pressure, and theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give the desiredcompound (6.2 g).

REFERENCE EXAMPLE 2 Preparation of 3-(cyclohexen-1-yl)aniline(Intermediate 2)

(1) Cyclohexanone (1 ml) and 2,6-di-tert-butyl-4-methylpyridine (2.4 g)are dissolved in methylene chloride (10 ml), and thereto is addedtrifluoromethanesulfonic anhydride (1.8 ml), and the mixture is stirredat room temperature for 18 hours. The insoluble materials are removed byfiltration, and the filtrate is evaporated under reduced pressure. Theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give(cyclohexen-1-yl)trifluoromethyl sulfonate (1.3 g).

(2) The above product (1.3 g) is dissolved in ethylene glycol dimethylether (10 ml), and thereto are added 3-nitrophenylboronic acid (1.3 g),tetrakis(triphenylphosphine)palladium (0) (330 mg), lithium chloride(720 mg) and 2M aqueous sodium carbonate (8 ml), and the mixture isheated under reflux for 3 hours. To the mixture is added ethyl acetate,and the organic layer is washed with water, and the solvent isevaporated under reduced pressure. The residue is purified by silica gelcolumn chromatography (eluent: gradient from 0% to 100% hexane/ethylacetate) to give 3-(cyclohexen-1-yl)-1-nitrobenzene (700 mg).

(3) The above product (100 mg) is dissolved in ethanol (5 ml), andthereto are added reduced iron (140 mg), ammonium chloride (53 mg) andwater (5 ml), and the mixture is heated under reflux for one hour. Theinsoluble materials are removed by filtration, and the solvent isevaporated under reduced pressure. The residue is purified by silica gelcolumn chromatography (eluent: gradient from 0% to 100% hexane/ethylacetate) to give the desired compound (60 mg).

REFERENCE EXAMPLE 3 Preparation of 3-cyclohexylaniline (Intermediate 3)

3-(Cyclohexen-1-yl)-1-nitrobenzene(7.5 g) is dissolved in ethanol (150ml), and thereto is added 10% palladium on carbon (750 mg), and themixture is subjected to catalytic hydrogenation at 25° C. The catalystis removed by filtration, and the solvent is evaporated under reducedpressure. The residue is purified by silica gel column chromatography(eluent: gradient from 0% to 100% hexane/ethyl acetate) to give thedesired compound (5.1 g).

REFERENCE EXAMPLE 4 Preparation of4-[2-(tert-butoxycarbonylamino)ethoxy]-N-(3-iodophenyl)-3-methoxyphenylacetamide(Intermediate 4)

A mixture of Intermediate 1 (8.4 g), 1,2-dibromethane (160 ml), 40%aqueous potassium hydroxide solution (45 ml) and 40% aqueoustetrabutylammonium hydroxide solution (4.5 ml) is heated with stirringat 40° C. for 18 hours. The reaction solution is washed with water, andthe organic layer is dried over sodium sulfate, and the solvent isevaporated under reduced pressure. The residue is dissolved indimethylformamide (45 ml), and thereto is added potassium phthalimide(1.9 g). The mixture is stirred at 50° C. for 18 hours. The reactionsolution is poured into ice-water, and the mixture is extracted withchloroform. The extract is washed with water, and the solvent isevaporated under reduced pressure. The residue is dissolved in ethanol(50 ml), and thereto is added hydrazine monohydrate (600 mg), and heatedunder reflux for 3 hours. The insoluble materials are removed byfiltration, and the filtrate is concentrated, extracted with chloroform,washed with water, and the solvent is evaporated under reduced pressure.The residue is dissolved in chloroform (50 ml) and thereto is addeddi-tert-butyl dicarbonate (4.3 g). The mixture is stirred at 25° C. for18 hours, and the solvent is evaporated under reduced pressure. Theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give the desiredcompound (5.2 g).

REFERENCE EXAMPLE 5 Preparation of4-(2-bromoethoxy)-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide(Intermediate 5)

A mixture ofN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide(the compound of Example 20) (1.5 g), 1,2-dibromethane (15 ml), 40%aqueous potassium hydroxide solution (5 ml) and 40% aqueoustetrabutylammonium hydroxide solution (0.5 ml) is stirred at 50° C. for18 hours. The reaction solution is washed with water, and the organiclayer is dried over sodium sulfate, and the solvent is evaporated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give the desired compound (1.6 g).

REFERENCE EXAMPLE 6 Preparation of4-[2-(tert-butoxycarbonylamino)ethoxy]-N-[3-(4,4,5,5-tetramethyl-1,3-dioxaboran-2-yl)phenyl]-3-methoxyphenylacetamide(Intermediate 6)

Intermediate 4 (4.2 g) is dissolved in dimethylformamide (42 ml), andthereto are added bis(pinacolato)diboron (6 g), potassium acetate (2.35g), 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium complex (652mg), and the mixture is heated with stirring at 80° C. for 24 hoursunder argon atmosphere. To the reaction solution is added ethyl acetate,and the mixture is washed with water, 1 M aqueous sodium hydroxidesolution, and the organic layer is dried over sodium sulfate. Thesolvent is evaporated under reduced pressure, and the residue ispurified by silica gel column chromatography (eluent: gradient from 0%to 100% hexane/ethyl acetate) to give the desired compound (4 g).

REFERENCE EXAMPLE 7 Preparation of4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxyphenylacetic acidpentafluorophenyl ester (Intermediate 7)

(1) 4-(2-Azidoethoxy)-3-methoxyphenylacetic acid methyl ester (72 g),which is prepared by the method disclosed in EP 0721939, is dissolved inethanol (1 L), and thereto is added 10% palladium on carbon (5 g), andthe mixture is subjected to catalytic hydrogenation at 25° C. Thecatalyst is removed by filtration, and the solvent is evaporated underreduced pressure to give 4-(2-aminoethoxy)-3-methoxyphenylacetic acidmethyl ester. This product is dissolved in chloroform (500 ml), andthereto is added di-tert-butyl dicarbonate (90 g), and the mixture isstirred at 25° C. for 18 hours. The solvent is evaporated under reducedpressure, and the residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give 4-[2-(tert-butoxycarbonylamino)ethoxy]-3methoxyphenylacetic acidmethyl ester (43.7 g).

(2) The above ester compound is dissolved in methanol (350 ml), andthereto is added 1 M aqueous sodium hydroxide solution (350 ml), and themixture is stirred at 25° C. for 18 hours. The solvent is evaporatedunder reduced pressure, and the residue is acidified with acetic acid,and the mixture is extracted with ethyl acetate. The solvent isevaporated under reduced pressure, and the residue is dissolved inmethylene chloride (500 ml), and thereto are added pentafluorophenol (22g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23g). The mixture is stirred at 25° C. for 18 hours, and the reactionsolution is washed with water, and the solvent is evaporated underreduced pressure, and the residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give the desired compound (42.3 g).

REFERENCE EXAMPLE 8 Preparation of7-amino-1-oxo-2-(2-pyridylmethyl)-1,2,3,4-tetrahydronaphthalene(Intermediate 8)

(1) 7-Nitro-1-tetralone (500 mg), pyridine-2-aldehyde (315 mg),piperidine (0.15 ml) and acetic acid (0.4 ml) are dissolved in toluene(10 ml), and the mixture is heated under reflux for 12 hours. Thereaction solution is washed with water, and the organic layer is driedover sodium sulfate. The solvent is evaporated under reduced pressure.The residue is purified by silica gel chromatography (eluent: gradientfrom 0% to 100% hexane/ethyl acetate) to give7-nitro-1-oxo-2-(2-pyridylmethylidene)-1,2,3,4-tetrahydronaphthalene(140 mg).

(2) The above product (140 mg) is dissolved in ethanol (5 ml), andthereto is added 10% palladium on carbon (20 mg), and the mixture issubjected to catalytic hydrogenation at 25° C. The catalyst is removedby filtration, and the solvent is evaporated. The residue is purified bysilica gel column chromatography (eluent: gradient of 0% to 100%hexane/ethyl acetate) to give Intermediate 8 (35 mg).

REFERENCE EXAMPLE 9 Preparation of 6-amino-N-benzylindole (Intermediate9)

(1) 6-Nitroindole (1.0 g) and benzyl chloride (2.2 g) are dissolved indimethylsulfoxide (10 ml), and thereto is added potassium hydroxide (1.0g), and the mixture is stirred at room temperature for 12 hours. To themixture is added ethyl acetate, and the organic layer is washed withwater, dried over sodium sulfate, and the solvent is evaporated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give N-benzyl-6-nitroindole (1.4 g).

(2) The above product (1.4 g) is dissolved in ethanol (20 ml), andthereto are added reduced iron (1.7 g), ammonium chloride (660 mg) andwater (10 ml), and the mixture is heated under reflux for one hour. Theinsoluble materials are removed by filtration, and the solvent isevaporated under reduced pressure. The residue is purified by silica gelcolumn chromatography (eluent: gradient from 0% to 100% hexane/ethylacetate) to give the title compound (660 mg).

EXAMPLE 1 Preparation ofN-(3-cyclohexylphenyl)-4-hydroxy-3-methoxyphenylacetamide

Intermediate 1 (850 mg) and tetrakis(triphenylphosphine)-palladium (0)(250 mg) are dissolved in tetrahydrofuran (16 ml), and thereto is addeda 0.5 M tetrahydrofuran solution (20 ml) of cyclohexylzinc bromide underargon atmosphere at room temperature, and the mixture is stirred for 18hours. A saturated aqueous ammonium chloride solution is added to thereaction solution, and the mixture is extracted with ethyl acetate. Theorganic layer is dried over sodium sulfate, and the solvent isevaporated under reduced pressure. The residue is purified by silica gelcolumn chromatography (eluent: gradient from 0% to 100% hexane/ethylacetate) to give the desired compound (120 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 1.18–1.85 (10H, m), 2.45 (1H, m), 3.65 (2H,s), 3.90 (3H, s), 5.67 (1H, s), 6.81–6.82 (2H, m), 6.93 (1H, s), 6.95(1H, d), 7.07 (1H, s), 7.17–7.25 (3H, m).

EXAMPLES 2 TO 6

Using various zinc bromides instead of cyclohexyl zinc bromide inExample 1, the compounds as listed in Table 7 are obtained in a similarmanner to Example 1.

TABLE 7

Ex. No. R⁴ 2

3

4

5

6

EXAMPLES 7 TO 8

Instead of 4-hydroxy-N-(3-iodophenyl)-3-methoxyphenylacetamide(Intermediate 1) in Example 1, various phenylacetamide derivatives aretreated in a similar manner to Example 1 to give the compounds as listedin Table 8.

TABLE 8

Ex. No. R¹ 7 F 8 Cl

EXAMPLE 9 Preparation ofN-[3-(cyclohexen-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide

4-Hydroxy-3-methoxyphenylacetic acid pentafluorophenyl ester (60 mg) andIntermediate 2 (60 mg) are dissolved in ethyl acetate, and the mixtureis stirred at 60° C. for 18 hours. The solvent is evaporated underreduced pressure, and the residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give the title compound (50 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 1.63 (2H, m), 1.75 (2H, m), 2.17 (2H, m),2.35 (2H, m), 3.67 (2H, s), 3.90 (3H, s), 5.65 (1H, s), 6.08 (1H, s),6.82 (2H, m), 6.95 (1H, d), 7.05–7.15 (2H, m), 7.17–7.38 (3H, m).

EXAMPLES 10 TO 28

Instead of 3-(cyclohexen-1-yl)aniline (Intermediate 2) in Example 9,various aniline derivatives are treated in a similar manner to Example 9to give the compounds as listed in Table 9, Table 10 and Table 11.

TABLE 9

Ex. No. R⁴ 10

11

12

13

14

15

16

17

18

19

20

TABLE 10

Ex. No. R⁴ 21

22

23

24

25

26

TABLE 11 Ex. No. Compound 27

28

EXAMPLES 29 TO 32

Instead of 4-hydroxy-3-methoxyphenylacetic acid pentafluorophenyl esterand Intermediate 2 in Example 9, various pentafluorophenyl esters andIntermediate 3 are used respectively, and treated in a similar manner toExample 9 to give the compounds as listed in Table 12.

TABLE 12

Ex. No. R¹ R³ 29 NO₂ H 30 MeO Ph 31 t-Bu t-Bu 32 MeO CHO

EXAMPLE 33 Preparation of3-amino-4-benzyloxy-N-(3-cyclohexylphenyl)phenylacetamide

A mixture of N-(3-cyclohexylphenyl)-4-hydroxy-3-nitrophenylacetamide(the compound of Example 29) (300 mg), benzyl bromide (287 mg),potassium carbonate (500 mg) and acetone (10 ml) is heated under refluxfor 18 hours. After cooling, water is added to the mixture, and themixture is extracted with ethyl acetate. The organic layer is dried oversodium sulfate, and the solvent is evaporated under reduced pressure.The residue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give4-benzyloxy-N-(3-cyclohexylphenyl)-3-nitrophenylacetamide (320 mg). Thisproduct is dissolved in ethanol (5 ml), and thereto are added reducediron (200 mg), ammonium chloride (80 mg) and water (5 ml), and themixture is heated under reflux for one hour. The reaction solution isfiltered through Celite, and the filtrate is concentrated, and theresidue is dissolved in chloroform. The organic layer is washed withwater, dried over sodium sulfate, and the solvent is evaporated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give the desired compound (240 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 1.20–1.45 (5H, m), 1.70–1.90 (5H, m), 2.44(1H, m), 3.59 (2H, s), 5.10 (2H, s), 6.63 (1H, dd), 6.69 (1H, d), 6.86(1H, d), 6.92 (1H, d), 7.10 (1H, m), 7.18–7.24 (3H, m), 7.30–7.46 (5H,m).

EXAMPLE 34 Preparation ofN-(3-cyclohexylphenyl)-4-hydroxy-3-(methanesulfonylamino)phenylacetamide

3-Amino-4-benzyloxy-N-(3-cyclohexylphenyl)phenylacetamide (the compoundof Example 33) (200 mg) is dissolved in pyridine (5 ml), and thereto isadded dropwise methanesulfonyl chloride (111 mg), and the mixture isstirred for 0.5 hour. Water is added to the mixture, and the mixture isextracted with ethyl acetate. The organic layer is dried under sodiumsulfate, and the solvent is evaporated under reduced pressure. Theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give4-benzyloxy-N-(3-cyclohexylphenyl)-3-methanesulfonylaminophenyl-acetamide(200 mg). This product is dissolved in ethanol (10 ml), and thereto isadded 10% palladium on carbon (20 mg). The mixture is subjected tocatalytic hydrogenation at 25° C. The catalyst is removed by filtration,and the solvent is evaporated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent: gradient from 0%to 10% chloroform/methanol) to give the desired compound (120 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 1.20–1.46 (5H, m), 1.65–1.85 (5H, m), 2.42(1H, m), 2.94 (3H, s), 3.46 (2H, s), 6.82 (1H, d), 6.87 (1H, d), 6.99(1H, dd), 7.13–7.19 (2H, m), 7.36 (1H, d), 7.46 (1H, s), 9.99 (1H, s).

EXAMPLE 35 Preparation of4-hydroxy-3-methoxy-N-(3-phenylphenyl)phenylacetamide

Intermediate 1 (500 mg), phenylboronic acid (300 mg),tetrakis(triphenylphosphine)palladium (0) (150 mg) are dissolved intetrahydrofuran (20 ml), and thereto are added cesium carbonate (850 mg)and water (10 ml). The mixture is heated under reflux for 18 hours underargon atmosphere. The reaction solution is extracted with ethyl acetate,and the organic layer is dried over sodium sulfate, and the solvent isevaporated under reduced pressure. The residue is purified by silica gelcolumn chromatography (eluent: gradient from 0% to 100% hexane/ethylacetate) to give the desired compound (360 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 3.69 (2H, s), 3.91 (3H, s), 5.65 (1H, s),6.81–6.87 (2H, m), 6.96 (1H, d), 7.16 (1H, s), 7.29–7.50 (6H, m), 7.56(2H, m), 7.62 (1H, s).

EXAMPLE 36 Preparation of4-hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]-phenylacetamide

A mixture of Intermediate 1 (2.5 g), ethynylbenzene (800 mg), copper (I)iodide (124 mg), bis(triphenylphosphine)palladium (II) dichloride (1.37g), triethylamine (19.0 g) and acetonitrile (20 ml) is heated withstirring at 50° C. under argon atmosphere. The solvent is evaporatedunder reduced pressure, and the residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give the desired compound (1.8 g).

¹H-NMR (300 MHz, CDCl₃, δ): 3.68 (2H, s), 3.91 (3H, s), 5.67 (1H, s),6.82–6.84 (2H, m), 6.96 (1H, d), 7.10 (1H, s), 7.25–7.35 (5H, m),7.46–7.53 (4H, m).

EXAMPLE 37 Preparation of4-hydroxy-3-methoxy-N-[3-[2-(2-trifluoromethylphenyl)-ethynyl]phenyl]phenylacetamide

A mixture of N-(3-ethynylphenyl)-4-hydroxy-3-methoxypheny-acetamide (thecompound of Example 19) (200 mg), 1-trifluoromethyl-2-iodobenzene (280mg), copper (I) iodide (19 mg), bis(triphenylphosphine)palladium (II)dichloride (70 mg), triethylamine (1 g) and acetonitrile (3 ml) isheated with stirring at 50° C. under argon atmosphere for 18 hours. Thesolvent is evaporated under reduced pressure, and the residue ispurified by silica gel column chromatography (eluent: gradient from 0%to 100% hexane/ethyl acetate) to give the desired compound (120 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 3.68 (2H, s), 3.92 (3H, s), 5.65 (1H, s),6.83 (2H, m), 6.96 (1H, d), 7.11 (1H, s), 7.25–7.35 (2H, m), 7.42 (1H,m), 7.44–7.60 (3H, m), 7.52–7.71 (2H, m).

EXAMPLES 38 TO 53

Instead of 1-trifluoromethyl-2-iodobenzene in Example 37, variousiodobenzene derivatives are treated in a similar manner to Example 37 togive the compounds as listed in Table 13.

TABLE 13

Ex. No. R⁸ 38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

EXAMPLE 54 Preparation of4-hydroxy-3-methoxy-N-[3-(2-phenylethyl)phenyl]-phenylacetamide

4-Hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]phenylacetamide (thecompound of Example 36) (250 mg) is dissolved in ethyl acetate (10 ml),and thereto is added 10% palladium on carbon (25 mg), and the mixture issubjected to catalytic hydrogenation at 25° C. The catalyst is removedby filtration, and the solvent is evaporated under reduced pressure. Theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give the desiredcompound (200 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 2.86 (4H, s), 3.66 (2H, s), 3.90 (3H, s),5.68 (1H, s), 6.81–7.01 (4H, m), 6.96 (1H, s), 7.09–7.42 (7H, m), 7.72(1H, d).

EXAMPLE 55 Preparation of4-hydroxy-3-methoxy-N-[4-(2-phenylethyl)phenyl]phenylacetamide

Instead of the compound of Example 36, the compound of Example 22 istreated in a similar manner to Example 54 to give the desired compound.

EXAMPLE 56 Preparation of4-hydroxy-3-methoxy-N-[3-[(Z)-2-phenylvinyl]phenyl]-phenylacetamide

4-Hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]phenylacetamide (150mg) obtained in Example 36 is dissolved in ethyl acetate (10 ml), andthereto is added Lindlar catalyst (5% lead-poisoned palladium-calciumcarbonate) (15 mg), and the mixture is subjected to catalytichydrogenation at 25° C. The catalyst is removed by filtration, and thesolvent is evaporated under reduced pressure. The residue is purified bysilica gel column chromatography (eluent: gradient from 0% to 100%hexane/ethyl acetate) to give the desired compound (50 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 3.62 (2H, s), 3.88 (3H, s), 5.68 (1H, s),6.51 (1H, d), 6.59 (1H, d); 6.76–7.26 (12H, m), 7.44 (1H, d).

EXAMPLE 57 Preparation ofN-[3-(N-cyclohexylcarbamoyl)phenyl]-4-hydroxy-3-methoxyphenylacetamide

A mixture of N-(3-carboxyphenyl)-4-hydroxy-3-methoxyphenylacetamide (500mg), pentafluorophenol (305 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg) andmethylene chloride (10 ml) is stirred at 25° C. for 18 hours. Thereaction solution is washed with water, and the solvent is evaporatedunder reduced pressure. To the residue are added ethyl acetate (10 ml)and cyclohexylamine (174 mg), and the mixture is heated with stirring at60° C. for 18 hours. The solvent is evaporated and the residue ispurified by silica gel column chromatography (eluent: gradient from 0%to 100% hexane/ethyl acetate) to give the desired compound (600 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 1.17–1.51 (4H, m), 1.63–1.88 (4H, m),1.95–2.07 (2H, m), 3.68 (2H, s), 3.90 (3H, s), 3.94 (1H, m), 5.70 (1H,s), 6.03 (1H, d), 6.81 (2H, m), 6.94 (1H, d), 7.32–7.46 (3H, m), 7.68(1H, d), 7.74 (1H, s).

EXAMPLE 58 Preparation of4-(2-aminoethoxy)-N-(3-cycloheptylphenyl)-3-methoxyphenylacetamidehydrochloride

3-Methoxy-4-(2-phthalimidoethoxy)phenylacetic acid pentafluorophenylester (690 mg) and 3-cycloheptylaniline (500 mg) are dissolved in ethylacetate (10 ml), and the mixture is heated with stirring at 60° C. for18 hours. The solvent is evaporated under reduced pressure, and theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to giveN-(3-cycloheptylphenyl)-3-methoxy-4-(2-phthalimidoethoxy)phenylacetamide(500 mg). This product is dissolved in ethanol (10 ml), and thereto isadded hydrazine monohydrate (610 mg), and the mixture is heated underreflux for 2 hours. The insoluble materials are removed by filtration,and the solvent is evaporated under reduced pressure. To the residue isadded water, and the mixture is extracted with chloroform. The organiclayer is dried over sodium sulfate, and the residue is purified bysilica gel column chromatography (eluent: gradient from 0% to 30%chloroform/methanol), and treated with 10% hydrogen chloride-methanol togive the desired compound (170 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 1.47–1.82 (12H, m), 2.60 (1H, m), 3.16(2H, t), 3.57 (2H, s), 3.78 (3H, s), 4.13 (2H, t), 6.86 (2H, m), 7.00(2H, m), 7.16 (1H, t), 7.39 (1H, d), 7.48 (1H, s), 8.12 (3H, s), 10.17(1H, s).

EXAMPLES 59 TO 62

Instead of 3-cycloheptylaniline in Example 58, the correspondingcompounds are treated in a similar manner to Example 58 to give thecompounds as listed in Table 14.

TABLE 14

Ex. No. R⁴ 59

60

61

62

EXAMPLE 63 Preparation of4-(2-aminoethoxy)-3-methoxy-N-(3-phenylphenyl)phenylacetamidehydrochloride

Intermediate 4 (500 mg) is dissolved in tetrahydrofuran (10 ml), andthereto are added tetrakis(triphenylphosphine)palladium (0) (110 mg),phenylboronic acid (230 mg), cesium carbonate (1.2 g) and water (2 ml),and the mixture is heated under reflux for 18 hours under argonatmosphere. The solvent is evaporated under reduced pressure, and theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxy-N-(3-phenylphenyl)phenylacetamide(350 mg). This product is treated with 10% hydrogen chloride-methanol togive the desired compound (210 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 3.18 (2H, t), 3.61 (2H, s), 3.79 (3H, s),4.11 (2H, t), 6.88 (1H, m), 7.01 (2H, m), 7.30–7.50 (5H, m), 7.60 (3H,m), 7.85–8.00 (4H, m), 10.25 (1H, s).

EXAMPLES 64 TO 68

Instead of phenylboronic acid in Example 63, various boronic acidderivatives are treated in a similar manner to Example 63 to give thecompounds as listed in Table 15.

TABLE 15

Ex. No. R⁴ 64

65

66

67

68

EXAMPLE 69 Preparation of4-acetoxy-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide

N-[3-(4-tert-Butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide(100 mg) obtained in Example 20, triethylamine (94 mg) and4-dimethylaminopyridine (5 mg) are dissolved in methylene chloride (5ml), and thereto is added dropwise acetyl chloride (40 mg) underice-cooling. The mixture is stirred at 25° C. for 18 hours, and thereaction solution is washed with water. The organic layer is dried oversodium sulfate, and the solvent is evaporated under reduced pressure.The residue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give the desiredcompound (90 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 0.78, 0.86 (9H, m), 1.0–1.25 (3H, m),1.30–1.93 (5H, m), 2.20 (1H, m), 2.32 (3H, s), 2.40, 2.98 (1H, m), 3.70(2H, s), 3.83 (3H, s), 6.83–7.42 (8H, m).

EXAMPLES 70 TO 71

Instead of acetyl chloride in Example 69, various acyl chloridederivatives are treated in a similar manner to Example 69 to give thecompounds as listed in Table 16.

TABLE 16 Ex. No. Compound 70

71

EXAMPLE 72 Preparation ofN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-carboxy-methyloxy-3-methoxyphenylacetamide

N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide(130 mg) and ethyl bromoacetate (84 mg) are dissolved in acetone, andthereto is added potassium carbonate (180 mg), and the reaction solutionis heated under reflux for 18 hours. The reaction solution is filtered,and the filtrate is concentrated. The residue is purified by silica gelcolumn chromatography (eluent: gradient from 0% to 100% hexane/ethylacetate) to giveN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-ethoxycarbonylmethyloxy3-methoxyphenylacetamide (120 mg). This product is dissolved in methanol(2 ml), and thereto is added 2 M aqueous sodium hydroxide solution (1ml), and the mixture is stirred at 25° C. for 1 hour. The mixture isneutralized with acetic acid, and water is added thereto. The mixture isextracted with chloroform, and the organic layer is dried over sodiumsulfate. The solvent is evaporated under reduced pressure, and theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 25% chloroform/methanol) to give the desiredcompound (45 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 0.79, 0.87 (9H, m), 1.05–1.95 (8H, m), 2.20(1H, m), 2.38, 2.98 (1H, m), 3.68 (2H, s), 3.90 (3H, s), 4.69 (2H, s),6.84–7.44 (8H, m).

EXAMPLE 73 Preparation ofN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-[2-[N-(2-hydroxyethyl)amino]ethoxy]-3-methoxyphenylacetamide

Intermediate 5 (200 mg), 2-aminoethanol (122 mg) and triethylamine (45mg) are dissolved in acetonitrile (5 ml), and the mixture is heatedunder reflux for 18 hours. To the reaction solution is added chloroform,and the mixture is washed with water. The organic layer is dried oversodium sulfate, and the solvent is evaporated under reduced pressure.The residue is purified by silica gel column chromatography (eluent:gradient from 0% to 20% chloroform/methanol) to give the desiredcompound (170 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 0.79, 0.87 (9H, m), 1.05–2.25 (9H, m), 2.40,2.98 (1H, m), 2.90 (2H, t), 3.10 (2H, t), 3.68 (2H, s), 3.71 (2H, t),3.86 (3H, s), 4.16 (2H, t), 6.81–7.42 (8H, m).

EXAMPLE 74 Preparation ofN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxy-4-[2-(N-methylamino)ethoxy]phenylacetamide

Instead of 2-aminoethanol in Example 73, methylamine is treated in asimilar manner to Example 73 to give the desired compound.

EXAMPLE 75 Preparation ofN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-[2-(N-formylamino)ethoxy]-3-methoxyphenylacetamide

Formic acid (30 mg) is slowly added to acetic anhydride (75 mg), and themixture is heated with stirring at 60° C. for 2 hours. To the mixture isadded dry tetrahydrofuran (0.2 ml), and further added4-(2-aminoethoxy)-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide(100 mg) obtained in Example 62 at −20° C. The mixture is stirred atroom temperature for 3 hours. The solvent is evaporated under reducedpressure, and the residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give the desired compound (80 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 0.79, 0.86 (9H, m), 1.03–1.94 (8H, m), 2.20(1H, m), 2.40, 2.98 (1H, m), 3.67 (2H, s), 3.74 (2H, q), 3.88 (3H, s),4.12 (2H, t), 6.27 (1H, m), 6.81–7.45 (8H, m), 8.24 (1H, s).

EXAMPLES 76 TO 79

Instead of cyclohexylzinc bromide in Example 1, various zinc bromidecompounds are treated in a similar manner to Example 1 to give thecompounds as listed in Table 17.

TABLE 17

Ex. No. R⁴ 76

77

78

79

EXAMPLES 80 TO 96

Instead of 3-(cyclohexen-1-yl)aniline (Intermediate 2) in Example 9,various aniline derivatives are treated in a similar manner to Example 9to give the compounds as listed in Table 18.

TABLE 18

Ex. No. R⁴ R⁵ 80

H 81

H 82

H 83

H 84

H 85

H 86

H 87

H 88

H 89

H 90

H 91 —Ph t-BuCOOCH₂— 92 —Ph Me 93

H 94

H 95

H 96

H

EXAMPLE 97 Preparation ofN-(2-benzylphenyl)-4-hydroxy-3-methoxyphenylacetamide

The corresponding strating compounds are treated in a similar manner toExample 9 to give the desired compounds.

EXAMPLES 98 TO 99

Instead of 3-(cyclohexen-1-yl)aniline (Intermediate 2) and4-hydroxy-3-methoxyphenylacetic acid pentafluorophenyl ester in Example9, 3-(4-tert-butylcyclohexan-1-yl)aniline and various pentafluorophenylesters are used respectively and treated in a similar manner to Example9 to give the compounds as listed in Table 19.

TABLE 19

Ex. No. R² R³ 98 H I 99 Me H

EXAMPLES 100 TO 105

Instead of phenyboronic acid in Example 35, various arylboronic acidderivatives are treated in a similar manner to Example 35 to give thecompounds as listed in Table 20.

TABLE 20

Ex. No. R⁴ 100

101

102

103

104

105

EXAMPLE 106 Preparation of4-hydroxy-3-methoxy-N-(4-phenylphenyl)phenylacetamide

Instead of Intermediate 1 in Example 35,4-hydroxy-N-(4-iodophenyl)-3-methoxyphenylacetamide is treated in asimilar manner to Example 35 to give the desired compound.

EXAMPLE 107 Preparation of4-hydroxy-3-methoxy-N-[2-(2-phenylethynyl)phenyl]-phenylacetamide

Instead of Intermediate 1 in Example 36,4-hydroxy-N-(2-iodophenyl)-3-methoxyphenylacetamide is treated in asimilar manner to Example 36 to give the desired compound.

EXAMPLES 108 TO 112

Instead of 1-trifluoromethyl-2-iodobenzene in Example 37, variousiodobenzene derivatives are treated in a similar manner to Example 37 togive the compounds as listed in Table 21.

TABLE 21

Ex. No. R⁸ 108

109

110

111

112

EXAMPLES 113 TO 116

Instead of4-hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]-phenylacetamide inExample 54, various ethynyl derivatives are treated in a similar mannerto Example 54 to give the compounds as listed in Table 22.

TABLE 22

Ex. No. R⁸ 113

114

115

116

EXAMPLE 117 Preparation of4-hydroxy-3-methoxy-N-[2-(2-phenylethyl)phenyl]phenylacetamide

Instead of4-hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]-phenylacetamide (thecompound of Example 36) in Example 54,4-hydroxy-3-methoxy-N-[2-(2-phenylethynyl)phenyl]phenylacetamide (thecompound of Example 107) is treated in a similar manner to Example 54 togive the desired compound.

EXAMPLE 118 Preparation of4-hydroxy-3-methoxy-N-[2-[(Z)-2-phenylvinyl]phenyl]-phenylacetamide

Instead of4-hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]-phenylacetamide (thecompound of Example 36) in Example 56,4-hydroxy-3-methoxy-N-[2-(2-phenylethynyl)phenyl]phenylacetamide (thecompound of Example 107) is treated in a similar manner to Example 56 togive the desired compound.

EXAMPLE 119 Preparation of4-acetoxy-3-methoxy-N-(3-phenylphenyl)phenylacetamide

Instead ofN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamidein Example 69, the compound of Example 35 is treated in a similar mannerto Example 69 to give the desired compound.

EXAMPLE 120 Preparation of4-hydroxy-3-methoxyphenyl-N-[3-(pyrrol-2-yl)phenyl]-phenylacetamide

The compound of Example 101 (100 mg) is dissolved in 30% hydrochloricacid-ethanol, and the mixture is stirred at 50° C. for 10 minutes. Thesolvent is evaporated under reduced pressure, and the residue ispurified by silica gel column chromatography (eluent: gradient from 0%to 10% chloroform/methanol) to give the desired compound (50 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 3.51 (2H, s), 3.74 (3H, s), 6.31 (1H, m),6.41 (1H, d), 6.69–6.72 (4H, m), 6.91 (1H, d), 7.25–7.38 (2H, m), 7.88(1H, s), 8.81 (1H, bs), 10.15 (1H, s), 11.49 (1H, s).

EXAMPLE 121 Preparation of4-(2-aminoethoxy)-3-methoxy-N-[3-(2-methoxycarbonylphenyl)phenyl]phenylacetamidehydrochloride

Intermediate 6 (526 mg) is dissolved in tetrahydrofuran (7 ml), andthereto are added tetrakis(triphenylphosphine)palladium (0) (115 mg),methyl 2-iodobenzoate (786 mg), cesium carbonate (978 mg) and water (1ml), and the mixture is heated under reflux for 42 hours under argonatmosphere. The solvent is evaporated under reduced pressure, and theresidue is purified by silica gel column chromatography (eluent:gradient from 0% to 100% hexane/ethyl acetate) to give4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxy-N-[3-(2-methoxycarbonylphenyl)phenyl]phenylacetamide(100 mg). This product is treated with 10% hydrogen chloride-methanol togive the desired compound (50 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 3.16 (2H, t), 3.58 (3H, s), 3.61 (2H, s),3.78 (3H, s), 4.12 (2H, t), 6.88 (1H, m), 7.01 (2H, m), 7.31–7.51 (4H,m), 7.60 (3H, m), 7.71 (1H, m), 7.73–8.40 (3H, bs), 10.34 (1H, s).

EXAMPLE 122 Preparation of4-(2-aminoethoxy)-3-methoxy-N-[3-(2-cyclohexylphenyl)-phenyl]phenylacetamidehydrochloride

Instead of methyl 2-iodobenzoate in Example 121,2-cyclohexyl-1-iodobenzene is treated in a similar manner to Example 121to give the desired compound.

EXAMPLES 123 TO 168

Instead of phenylboronic acid in Example 63, various boronic acidderivatives are treated in a similar manner to Example 63 to give thecompounds as listed in Table 23.

TABLE 23

Ex. No. R⁴ 123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

EXAMPLE 169 Preparation of4-(2-aminoethoxy)-N-[3-(3-tert-butylphenyl)phenyl]-3-methoxyphenylacetamidehydrochloride

Intermediate 7 (2.4 g) and 3-(tert-butyl)aniline (1.7 g) are dissolvedin ethyl acetate, and the mixture is heated under reflux for 18 hours.The solvent is evaporated under reduced pressure, and the residue ispurified by silica gel column chromatography (eluent: gradient from 0%to 100% hexane/ethyl acetate) to give4-[2-(tert-butoxycarbonylamino)ethoxy]-N-[3-(3-tert-butylphenyl)phenyl]-3-methoxyphenylacetamide(700 mg). This product is treated with 10% hydrogen chloride-methanol togive the desired compound (200 mg).

¹H-NMR (300 MHz, CD₃OD, δ): 1.33 (9H, s), 3.30 (2H, t), 3.71 (2H, s),3.85 (3H, s), 4.17 (2H, t), 6.94 (2H, m), 7.09 (1H, s), 7.28–7.37 (5H,m), 7.62 (2H, m), 7.95 (1H, s).

EXAMPLES 170 TO 202

Instead of 3-(tert-butyl)aniline in Example 169, various anilinederivatives are treated in a similar manner to Example 169 to give thecompounds as listed in Tables 24 and 25.

TABLE 24

Ex. No. R⁵ 170 6-F 171 5-F-6-MeO 172 6-Me 173 4-Me 174 2-Me 1752,4,6-(Me)₃ 176 4-MeO 177 6-MeO 178 5-CF₃ 179 4-CF₃O 180 4-Ph 1814-Me-5-Ph

TABLE 25

Ex. No. R⁴ X¹ 182

H 183

H 184

H 185

H 186

H 187

H 188

H 189

H 190

H 191

H 192

H 193

H 194

H 195

H 196

Me 197

H 198

H 199

H 200

H 201

H 202

H

EXAMPLE 203 Preparation of4-(2-aminoethoxy)-N-[3-(3-carboxyphenyl)phenyl]-3-methoxyphenylacetamidetrifluoroacetate

The compound of Example 146 (50 mg) is dissolved in methanol (3 ml), andthereto are added lithium hydroxide (10 mg) and water (1 ml), and themixture is stirred at 25° C. for 5 minutes. The solvent is evaporated,and the residue is purified by CHP-20 (manufactured by Mitsubishi KaseiCorporation; high porous styrene resin: 75 to 150 μm) (eluent: gradientfrom 40% to 70% (0.05% aqueous trifluoroacetic acid solution)/methanol)to give the desired compound (30 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 3.18 (2H, t), 3.61 (2H, s), 3.79 (3H, s),4.11 (2H, t), 6.88 (1H, d), 6.70–7.04 (2H, m), 7.38–7.45 (2H, m),7.57–7.65 (2H, m), 7.85–7.98 (3H, m), 8.15 (1H, s), 10.29 (1H, s).

EXAMPLE 204 Preparation of4-(2-aminoethoxy)-N-[3-[4-(1-carboxy-1-methylethyl)-phenyl]phenyl]-3-methoxyphenylacetamidetrifluoroacetate

Instead of the compound of Example 146 in Example 203, the compound ofExample 185 is treated in a similar manner to Example 203 to give thedesired compound.

EXAMPLE 205 Preparation ofN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-(2-hydroxyethyloxy)-3-methoxyphenylacetamide

N-[3-(4-tert-Butylcyclohexan-1-yl)phenyl]-4-ethoxycarbonylmethyloxy-3-methoxyphenylacetamide(240 mg), which is an intermediate of Example 72, is dissolved inethanol, and thereto is added sodium borohydride (35 mg), and themixture is stirred at room temperature for 2 hours. A saturated aqueousammonium chloride solution is added thereto, and the mixture isextracted with chloroform. The extracted is washed with water, and thesolvent is evaporated under reduced pressure. The residue is purified bysilica gel column chromatography (eluent: gradient from 0% to 100%hexane/ethyl acetate) to give the desired compound (110 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 0.79, 0.86 (9H, m), 1.0–1.30 (3H, m),1.33–1.48 (1H, m), 1.50–1.95 (4H, m), 2.20 (1H, m), 2.40, 2.98 (1H, m),3.67 (2H, s), 3.87 (3H, s), 3.96 (2H, t), 4.14 (2H, t), 6.83–7.42 (8H,m).

EXAMPLE 206 Preparation of4-(2-aminoethoxy)-N-[3-(4-tert-butylcyclohexan-1-yl)-phenyl]-3-(methanesulfonylamino)phenylacetamidehydrochloride

N-[3-(4-tert-Butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-nitrophenylacetamide(550 mg), which is prepared in a similar manner to Example 9, is treatedin a similar manner to Reference Example 4 to giveN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-nitro-4-(2-phthalimidoethoxy)phenylacetamide(500 mg). This product is dissolved in ethanol (10 ml), and thereto areadded reduced iron (240 mg), ammonium chloride (90 mg) and water (5 ml),and the mixture is heated under reflux for one hour. The insolublematerials are removed by filtration, and the solvent is evaporated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to give3-amino-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-(2-phthalimidoethoxy)phenylacetamide(140 mg). This product is dissolved in methylene chloride (5 ml), andthereto is added triethylamine (33 mg). To the mixture is added dropwisemethanesulfonyl chloride (33 mg), and the mixture is stirred for 2hours. The mixture is washed with water, and the solvent is evaporatedunder reduced pressure. The residue is purified by silica gel columnchromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate)to giveN-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methanesulfonylamino-4-(2-phthalimidoethoxy)phenylacetamide(70 mg). This product is treated with hydrazine monohydrate in a similarmanner to Example 58 to give the desired compound (30 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 0.76, 0.85 (9H, m), 1.0–1.90 (8H, m),2.10–2.20 (1H, m), 2.50, 2.94 (1H, m), 2.95 (3H, s), 3.30 (2H, m), 3.55(2H, s) 4.15 (2H, t), 6.85–7.60 (7H, m), 8.01 (3H, brs), 8.88 (1H, s),10.02 (1H, m).

EXAMPLE 207 Preparation of4-(2-aminoethoxy)-N-[3-[(E)-2-(3-methylphenyl)vinyl]-phenyl]-3-methoxyphenylacetamidehydrochloride

Intermediate 4 (1 g) is dissolved in dimethylformamide (10 ml), andthereto are added 3-methylvinylbenzene (826 mg), palladium (II) acetate(105 mg), tris(2-methylphenyl)phosphine (143 mg), tetra-n-butyl ammoniumchloride (130 mg), and the mixture is heated with stirring at 97° C. for18 hours under argon atmosphere. To the reaction solution is added ethylacetate, and the mixture is washed with water and 2 M hydrochloric acid.The organic layer is dried over sodium sulfate, and the solvent isevaporated under reduced pressure. The residue is purified by silica gelcolumn chromatography (eluent: gradient from 0% to 100% hexane/ethylacetate) to give4-[2-(tert-butoxycarbonylamino)-ethoxy]-3-methoxy-N-[3-[(E)-2-(3-methylphenyl)vinyl]phenyl]phenylacetamide(370 mg). This product is treated with 10% hydrogen chloride-methanol togive the desired compound (120 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 2.33 (3H, s), 3.17 (2H, t), 3.62 (2H, s),3.80 (3H, s), 4.14 (2H, t), 6.87–7.49 (12H, m), 7.87 (1H, s), 8.09 (3H,bs), 10.31 (1H, s).

EXAMPLES 208 TO 216

Instead of 3-methylvinylbenzene in Example 207, various vinylderivatives are treated in a similar manner to Example 207 to give thecompounds as listed in Table 26.

TABLE 26

Ex. No. R⁸ 208

209

210

211

212

213

214

215

216

EXAMPLE 217 Preparation of4-(2-aminoethoxy)-3-methoxy-N-[3-[2-(3-methylphenyl)-ethyl]phenyl]phenylacetamidehydrochloride

4-[2-(tert-Butoxycarbonylamino)ethoxy]-3-methoxy-N-[3-[(E)-2-(3-methylphenyl)vinyl]phenyl]phenylacetamide(100 mg) is dissolved in methanol (10 ml) and acetic acid (1 ml), andthereto is added 10% palladium on carbon (10 mg), and the mixture issubjected to catalytic hydrogenation at 50° C. The catalyst is removedby filtration, and the solvent is evaporated to give4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxy-N-[3-[2-(3-methylphenyl)ethyl]phenyl]phenylacetamide(80 mg). This product is treated with 10% hydrogen chloride-methanol togive the desired compound (50 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ): 2.26 (3H, s), 2.80 (4H, s), 3.17 (2H, t),3.57 (2H, s), 3.79 (3H, s), 4.13 (2H, t), 6.85–7.44 (10H, m), 7.51 (1H,s), 8.02 (3H, bs), 10.14 (1H, s).

EXAMPLES 218 TO 224

Instead of4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxy-N-[3-[(E)-2-(3-methylphenyl)vinyl]phenyl]phenylacetamidein Example 217, the corresponding derivatives are treated in a similarmanner to Example 217 to give the compounds as listed in Table 27.

TABLE 27

Ex. No. R⁸ 218

219

220

221

222

223

224

EXAMPLES 225 TO 235

Instead of 3-(tert-butyl)aniline in Example 169, Intermediate 8 ofReference Example 8, and 7-amino-1-oxo-1,2,3,4-tetrahydronaphthalenederivatives obtained in a similar manner to Reference Example 8 are usedand treated in a similar manner to Example 169 to give the compounds aslisted in Table 28.

TABLE 28

Ex. No. R⁹¹ 225

226

227

228

229

230

231

232

233

234

235

EXAMPLES 236 TO 247

Instead of 3-(cyclohexen-1-yl)aniline in Example 9, Intermediate 9 andaminoindole derivatives obtained in a similar manner to ReferenceExample 9 are used and treated in a similar manner to Example 9 to givethe compounds as listed in Tables 29 to 32.

TABLE 29

Ex. No. R⁹¹ 236

237

TABLE 30

Ex. No. R⁹¹ 238

239

240

241

242

243

TABLE 31

Ex. No. R⁹¹ 244

245

TABLE 32

Ex. No. R⁹¹ 246

247

EXAMPLE 248 Preparation of4-hydroxy-3-methoxy-N-[1-oxo-2-phenylmethylidene-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide

Instead of 3-(cyclohexen-1-yl)aniline (Intermediate 2) in Example 9,7-amino-1-tetralone is treated in a similar manner to Example 9. Theresulting4-hydroxy-3-methoxy-N-[1-oxo-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide(1 g) is dissolved in 30% hydrogen chloride-ethanol (5 ml), and theretois added benzaldehyde (433 mg). The mixture is stirred at 25° C. for 18hours. The precipitated crystals are collected by filtration, and washedwith diethyl ether to give the desired compound (700 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 2.89 (2H, t), 3.10 (2H, t), 3.69 (2H, s),3.89 (3H, s), 5.70 (1H, s), 6.80–6.85 (2H, m), 6.95 (2H, d), 7.22 (1H,d), 7.30–7.43 (5H, m), 7.66 (1H, d), 7.84 (1H, s), 8.09 (1H, dd).

EXAMPLE 249 Preparation of4-hydroxy-3-methoxy-N-[1-oxo-2-phenylmethyl-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide

The compound of Example 248 (500 mg) is dissolved in ethyl acetate (20ml), and thereto is added 10% palladium on carbon (50 mg), and themixture is subjected to catalytic hydrogenation at 25° C. The catalystis removed by filtration, and the solvent is evaporated under reducedpressure. The residue is purified by silica gel column chromatography(eluent: gradient from 0% to 100% hexane/ethyl acetate) to give thedesired compound (350 mg).

¹H-NMR (300 MHz, CDCl₃, δ): 1.67–1.81 (1H, m), 2.05–2.13 (1H, m),2.58–2.94 (4H, m), 3.43 (1H, dd), 3.67 (2H, s), 3.91 (3H, s), 5.67 (1H,s), 6.80–7.00 (3H, m), 7.25–7.35 (7H, m), 7.60 (1H, d), 8.01 (1H, dd).

EXAMPLE 250 Preparation of4-hydroxy-3-methoxy-N-[1-oxo-2-(2-methylpropylidene-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide

Instead of benzaldehyde in Example 248, isobutyl aldehyde is treated ina similar manner to Example 248 to give the desired compound.

EXAMPLE 251 Preparation of4-hydroxy-3-methoxy-N-[1-oxo-2-(2-methylpropyl)-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide

The compound of Example 250 is treated in a similar manner to Example249 to give the desired compound.

EXAMPLES 252 TO 255

Instead of 3-cycloheptylaniline in Example 58, 6-aminoindole derivativesare treated in a similar manner to Example 58 to give the compounds aslisted in Table 33.

TABLE 33

Ex. No. R⁹¹ 252

253

254

255

EXAMPLES 256 TO 258

Instead of phenylboronic acid in Example 35, the correspondingderivatives are treated in a similar manner to Example 35 to give thecompounds as listed in Table 34.

TABLE 34

Ex. No. R⁴ 256

257

258

EXAMPLES 259 TO 260

Instead of 3-(cyclohexen-1-yl)aniline in Example 9, the correspondingderivatives are treated in a similar manner to Example 9 to give thecompounds as listed in Table 35.

TABLE 35

Ex. No. R⁴ 259

260

The results of the analysis by HPLC of the compounds of the aboveExamples such as retention time (Rt) and the analysis conditions areshown in Table 36.

TABLE 36 Ex. No. Rt Conditions* 1 3.75 a 2 2.86 a 3 5.99 a 4 3.21 a 54.66 a 6 3.20 a 7 3.85 a 8 4.23 a 9 3.42 a 10 2.29 a 11 4.76 a 12 5.16 a13** 4.39, 4.64 a 14 2.15 a 15 3.27 a 16 1.50 a 17 2.47 a 18 2.01 a 192.21 a 20** 7.85, 9.13 a 21 2.86 a 22 3.25 a 23 2.75 a 24 3.27 a 25 1.43a 26 3.25 a 27 3.39 a 28 2.84 a 29 5.34 a 30 6.95 a 31 7.29 c 32 4.36 a33 3.09 a 34 3.08 a 35 2.76 a 36 3.36 a 37 3.77 a 38 4.03 a 39 4.67 a 403.02 a 41 3.38 a 42 5.33 a 43 5.00 a 44 5.43 a 45 3.54 a 46 3.33 a 473.46 a 48 3.82 a 49 4.46 a 50 4.62 a 51 4.53 a 52 4.82 a 53 6.89 a 543.20 a 55 3.16 a 56 3.15 a 57 2.22 a 58 5.52 b 59 4.09 b 60 3.75 b 614.18 b 62** 12.58, 16.39 b 63 2.68 b 64 7.50 b 65 2.67 b 66 3.11 b 673.96 b 68 3.54 b 69** 11.49, 13.45 a 70** 9.25, 10.46 c 71** 10.23,11.58 c 72** 6.31, 7.28 a 73** 12.22, 16.14 b 74** 2.78, 3.07 a 75**5.86, 6.73 a 76 4.57 a 77 5.19 a 78 4.14 a 79 3.87 a 80 7.41 a 81**3.44, 3.68 a 82** 3.99, 4.26 a 83** 4.26, 4.47 a 84 5.07 a 85** 5.30,5.66 a 86 2.25 d 87 2.40 d 88 3.10 f 89 3.05 f 90 2.41 d 91 9.76 d 924.93 d 93 2.78 a 94 4.97 d 95 2.67 d 96 3.60 d 97 2.68 a 98** 11.7, 14.0a 99** 9.72, 11.4 a 100 8.2 d 101 7.5 d 102 9.63 d 103 2.08 d 104 5.90 d105 4.20 d 106 2.76 a 107 7.8 d 108 3.06 a 109 2.28 a 110 2.75 a 1112.42 a 112 3.11 a 113 2.45 a 114 5.80 a 115 2.71 a 116 2.93 a 117 5.14 d118 5.8 d 119 8.22 d 120 2.15 d 121 2.24 d 122 5.57 d 123 2.33 d 1242.44 d 125 2.58 d 126 2.80 d 127 2.97 d 128 3.81 d 129 2.65 d 130 2.89 d131 2.55 d 132 3.03 d 133 3.57 d 134 3.20 d 135 3.86 d 136 4.04 d 1373.62 d 138 2.39 d 139 2.05 d 140 3.24 d 141 2.90 d 142 2.59 d 143 3.20 d144 4.14 d 145 4.01 d 146 2.41 d 147 4.70 d 148 2.05 d 149 2.06 d 1503.13 d 151 2.47 d 152 2.49 d 153 2.29 d 154 4.28 d 155 2.78 d 156 2.64 d157 2.21 d 158 2.48 d 159 2.74 i 160 4.69 f 161 3.88 g 162 3.2 d 1633.11 d 164 2.27 d 165 2.33 d 166 2.84 d 167 5.95 d 168 5.20 d 169 4.06 d170 2.26 d 171 2.63 d 172 2.21 d 173 2.44 d 174 2.16 d 175 2.41 d 1762.14 d 177 2.34 d 178 3.25 d 179 3.03 d 180 3.30 d 181 4.34 d 182 2.94 d183 6.53 d 184 3.67 d 185 3.17 d 186 2.28 d 187 2.56 d 188 2.35 d 1894.35 d 190 6.85 d 191 6.59 d 192 3.82 a 193 6.96 d 194 6.60 d 195 8.13 d196** 6.34, 8.31 d 197 2.64 h 198 3.40 f 199 6.19 f 200 4.18 f 201 6.36f 202 2.39 f 203 6.94 f 204 2.01 d 205** 6.19, 7.13 a 206 6.33 d 2073.43 d 208 2.91 d 209 3.11 d 210 3.51 d 211 3.77 d 212 3.98 d 213 6.09 f214 2.96 e 215 5.61 h 216 4.32 d 217 3.37 d 218 2.73 d 219 2.97 d 2203.74 d 221 5.74 f 222 2.96 d 223 4.05 h 224 4.00 d 225 2.79 d 226 3.19 d227 3.36 d 228 3.40 d 229 2.70 d 230 2.65 d 231 4.38 h 232 5.02 h 2335.02 h 234 3.33 h 235 4.11 d 236 2.96 a 237 3.69 a 238 2.73 a 239 2.96 a240 3.82 a 241 3.57 a 242 2.85 a 243 4.60 a 244 3.18 a 245 4.48 a 2463.31 a 247 4.77 a 248 3.17 a 249 3.23 a 250 3.04 a 251 3.39 a 252 2.30 d253 2.98 d 254 2.21 d 255 2.96 d 256 4.66 d 257 3.84 d 258 3.26 d 2592.28 d 260 2.41 d *Conditions for analysis: a: 65% acetonitrile/0.05%aqueous trifluoroacetic acid solution b: 45% acetonitrile/0.05% aqueoustrifluoroacetic acid solution c: 75% acetonitrile/0.05% aqueoustrifluoroacetic acid solution d: 50% acetonitrile/0.05% aqueoustrifluoroacetic acid solution e: 40% acetonitrile/0.05% aqueoustrifluoroacetic acid solution f: 30% acetonitrile/0.05% aqueoustrifluoroacetic acid solution g: 25% acetonitrile/0.05% aqueoustrifluoroacetic acid solution h: 20% acetonitrile/0.05% aqueoustrifluoroacetic acid solution i: 10% acetonitrile/0.05% aqueoustrifluoroacetic acid solution **Under the conditions of these Examples,diastereomers are separated.Preparation 1: Preparation of Tablets

4-(2-Aminoethoxy)-3-methoxy-N- 25 g[3-(2-phenylethynyl)phenyl]-phenylacetamide Lactose 70 g Corn strach 20g Crystalline cellulose 25 g Hydroxypropyl cellulose  3 g

The above components are mixed and kneaded in a conventional manner, andthe mixture is granulated and dried. To the mixture are added lightanhydrous silicic acid (0.7 g) and magnesium stearate (1.3 g), and themixture is further tabletted to give 1,000 tablets (each 145 mg).

Preparation 2: Preparation of Capsules

4-(2-Aminoethoxy)-3-methoxy-N-  50 g[3-(2-phenylethyl)phenyl]-phenylacetamide Lactose 117 g Corn strach  25g Hydroxypropyl cellulose  3.5 g Purified water 100 g

The above components are mixed and kneaded in a conventional manner, andthe mixture is granulated and dried. To the mixture are added lightanhydrous silicic acid (1.8 g) and magnesium stearate (2.7 g), and each200 mg of the resulting granule is packed into a capsule to give 1,000capsules.

Preparation 3: Preparation of Powder

4-(2-Aminoethoxy)-N-(3-cyclohexylphenyl)- 200 g3-methoxyphenyl-acetamide Lactose 770 g

The above components and light anhydrous silicic acid (5 g) are mixed ina conventional manner to give a powder preparation.

Preparation 4: Preparation of Ointment Using an Oleaginous Base

4-(2-Aminoethoxy)-3-methoxy-N-  0.1 g (3-phenylphenyl)phenyl-acetamidePlastibase 99.9 g

The above components are mixed in a conventional manner to give anointment.

Preparation 5: Preparation of Ointment Using an Aqueous Base

4-(2-Aminoethoxy)-N-[3-(4-tert-butylcyclohexan-1-yl)-  1 gphenyl]-3-methoxyphenylacetamide Polyethylene glycol 4000 44 gPolyethylene glycol 400 55 g

The above components are kneaded in a conventional manner with heating,if necessary, to give an ointment.

Preparation 6: Preparation of Patch

4-(2-Aminoethoxy)-3-methoxy-N-   10 g (3-phenylphenyl)-phenylacetamideEudragit E100 20.5 g Tributyl acetylcitrate 10.3 g Succinic acid  0.7 gPurified water 58.5 g

The above components are warmed, if necessary, and uniformly kneaded togive adhesive base containing a medicament for patches. The resultingbase is applied and flatted onto a suitable filmy support so as to givepatches containing 12.5 mg of said base per 1 cm² of the support, then,the base layer is dried and coated with a protective film, and cut intoa suitable shape of a suitable size corresponding to the dose (area: 2cm²) to give patches.

INDUSTRIAL APPLICABILITY

The compounds of the present invention exhibit a potent analgesicactivity with weak pungency, and they can be effective even in oraladministration. Therefore, the present compounds are useful as an agentfor treatment of neuropathic pain to which conventional analgesic agentsare ineffective, or pain caused by rheumatic arthritis, and as apreventive and/or a remedy for treatment of essential pruritus, allergyor nonallergic rhinitis, frequent urination and urinary incontinencewith overactive bladder, stroke, irritable bowel syndrome, respiratorydisorders such as asthma and chronic obstructive pulmonary disease,dermatitis, mucositis, gastric and duodenal ulcer, inflammatory boweldiseases and obesity.

1. An N-arylphenylacetamide derivative of the following formula (I):

(wherein R¹ is a C₁₋₆ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group, a C₁₋₆ alkylamino group, a di-(C₁₋₆alkyl)-amino group, a C₁₋₆ alkylsulfonylamino group, or anarylsulfonylamino group, R² is a hydrogen atom, a C₁₋₆ alkylcarbonylgroup, an arylcarbonyl group, —(CH₂)_(m)—N(R⁶)(R⁷), —(CH₂)_(m)OH or—(CH₂)_(q)COOH (in which m is an integer of 2 to 4, q is an integer of 1to 4, R⁶ is a hydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkylgroup, an amino-C₂₋₃ alkyl group, a formyl group, a C₁₋₃ alkylcarbonylgroup, a C₁₋₄ alkoxycarbonyl group, an arylcarbonyl group, or anaryl-C₁₋₃ alkyloxycarbonyl group, R⁷ is a hydrogen atom, a C₁₋₃ alkylgroup, a hydroxy-C₂₋₃ alkyl group, or an amino-C₂₋₃ alkyl group), R³ isa hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₄ alkoxygroup, an aryl group, or a formyl group, R⁴, which is located at themeta-position with respect to the group —N(X¹)—, is a C₆₋₁₀ alkyl group,a group of the following formula (A) or a group of the following formula(C), and the group of the formula (A) is a group of the formula:—Y—R⁸  (A) [in which Y is a single bond, a C₁₋₃ alkylene group, a C₂₋₃alkenylene group, a C₂₋₃ alkynylene group, —CO(CH₂)_(p)—, a C₂₋₃alkenylenecarbonyl group, —O—, —O—(CH₂)₂—, —O—(CH₂)₃—, or—CONH(CH₂)_(p)—, and p is an integer of 0 to 3, R⁸ is a monocyclic groupor a polycyclic group consisting of a 5- or 6-membered aromatic ringcontaining 0 to 3 heteroatoms selected from N, O and S, which mayoptionally be substituted by 1 to 3 atoms or groups selected from ahalogen, a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, a C₂₋₆ alkenyl, a C₂₋₆alkynyl, a trifluoromethyl, a trifluoroethyl, an aryl, an aryl-C₁₋₆alkyl, a C₁₋₆ alkoxy, a trifluoromethoxy, a C₃₋₇ cycloalkyloxy, anaryloxy, an aryl-C₁₋₃ alkyloxy, a C₁₋₆ alkylcarbonyl, a C₃₋₇cycloalkylcarbonyl, a formyl, a nitro, an amino, a di-(C₁₋₆ alkyl)amino,a cyano, a hydroxy, a C₁₋₃ alkylthio, a C₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl,a carboxy-C₁₋₃ alkyl, a C₁₋₄ alkoxycarbonyl, an aryl-C₁₋₃alkyloxycarbonyl, a carboxy and a sulfamoyl; a C₅₋₇ cycloalkenyl groupwhich may optionally be substituted by 1 to 4 atoms or groups selectedfrom a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, a halogen, a trifluoromethyl, aC₁₋₄ alkoxycarbonyl, an aryl, an aryl-C₁₋₆ alkyl, a C₁₋₃ alkoxy and ahydroxy; or a group of the formula (B):

(R^(a), R^(b), R^(c) and R^(d) are the same or different and each is ahydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a halogenatom, a trifluoromethyl group, a C₁₋₄ alkoxycarbonyl group, an arylgroup, an aryl-C₁₋₆ alkyl group, a C₁₋₃ alkoxy group or a hydroxy group,or when R^(a) and R^(b) attach to the same carbon atom, then thesegroups may combine to form an oxo group or a thioxo group, or when R^(c)and R^(d) attach to the same carbon atom, then these groups may combinetogether with said carbon atom to form a spiro ring, or 2 or 3 groupsselected from R^(a), R^(b) and R^(c) may combine to form a C₆₋₁₅polycycloalkyl group, and n is an integer of 1 to 6)], and the group ofthe formula (C) is a group of the formula:

(R^(e) and R^(f) are the same or different and each is a hydrogen atom,a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a halogen atom, atrifluoromethyl group, a C₁₋₄ alkoxycarbonyl group, an aryl group, anaryl-C₁₋₆ alkyl group, a C₁₋₃ alkoxy group or a hydroxy group, or whenR^(e) and R^(f) attach to the same carbon atom, then these groups maycombine together with said carbon atom to form a spiro ring, and Z is acarbon atom, an oxygen atom or a sulfur atom), R⁵ is a hydrogen atom, ahalogen atom, a C₁₋₆ alkyl group, a trifluoromethyl group, a C₁₋₃ alkoxygroup, a trifluoromethoxy group, a cyano group, a nitro group, an aminogroup, a hydroxy group, a carboxyl group, a C₁₋₆ alkylcarbonyloxymethylgroup, or an aryl group, or R⁴ and R⁵ may combine together with thebenzene ring to which they bond, and form a tetralone ring or an indolering, which is substituted by one group selected from a C₁₋₈ alkyl, aC₁₋₈ alkenyl, an aryl-C₁₋₃ alkyl, a C₃₋₇ cycloalkyl-C₁₋₃ alkyl, anarylsulfonyl, a C₁₋₈ alkylidene, a C₁₋₈ alkenylidene, an aryl-C₁₋₃alkylidene and a C₃₋₇ cycloalkyl-C₁₋₃ alkylidene, X¹ is a hydrogen atom,or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.
 2. The N-arylphenylacetamide derivative according to claim 1 ofthe following formula (I′):

wherein R^(1′) is a C₁₋₄ alkoxy group, a hydroxy group, a halogen atom,a nitro group, an amino group, a C₁₋₆ alkylsulfonylamino group or anarylsulfonylamino group, R^(2′) is a hydrogen atom, a C₁₋₆ alkylcarbonylgroup, an arylcarbonyl group or —(CH₂)₂—N(R^(6′))(R^(7′)), in whichR^(6′) is a hydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkylgroup, an amino-C₂₋₃ alkyl group, a formyl group, or an aryl-C₁₋₃alkyloxycarbonyl group, and R^(7′) is a hydrogen atom, a C₁₋₃ alkylgroup, a hydroxy-C₂₋₃ alkyl group, or an amino-C₂₋₃ alkyl group, R^(3′)is a hydrogen atom, a halogen atom, a C₁₋₄ alkyl group or an aryl group,R^(4′) is a C₆₋₁₀ alkyl group, a group of the following formula (A′), ora group of the following formula (C′), in which the group of the formula(A′) is a group of the formula:—Y′—R^(8′)  (A′) [in which Y′ is a single bond, —CH₂—, —(CH₂)₂—,—(CH₂)₃—, —CH═CH—, —C≡C—, —CO—, —COCH₂—, —CO(CH₂)₂—, —COCH═CH—, —O— or—O(CH₂)₂—, and R^(8′) is a monocyclic or polycyclic group consisting ofa 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selectedfrom N, O and S, which may optionally be substituted by 1 to 3 atoms orgroups selected from a halogen, a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, atrifluoromethyl, a trifluoroethyl, an aryl, an aryl-C₁₋₃ alkyl, a C₁₋₃alkoxy, a trifluoromethoxy, an aryloxy, a C₁₋₃ alkylcarbonyl, a C₃₋₇cycloalkylcarbonyl, a nitro, a cyano, a hydroxy, a C₁₋₃ alkylthio, aC₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, a carboxy-C₁₋₃ alkyl, a C₁₋₄alkoxycarbonyl and a carboxy; a C₅₋₇ cycloalkenyl group which mayoptionally be substituted by 1 to 4 atoms or groups selected from a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a fluorine, a trifluoromethyl, an aryl, a C₁₋₃alkoxy and a hydroxy; or a group of the formula (B′):

(R^(a′), R^(b′), R^(c′) and R^(d′) are the same or different and each isa hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorineatom, a trifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group or ahydroxy group, or when R^(a′) and R^(b′) attach to the same carbon atom,then these groups may combine to form an oxo group, or when R^(c′) andR^(d′) attach to the same carbon atom, then these groups may combinetogether with said carbon atom to form a spiro ring, or 2 or 3 groupsselected from R^(a′), R^(b′) and R^(c′) may combine to form a C₆₋₁₅polycycloalkyl group, and n′ is an integer of 1 to 5)], and the group ofthe formula (C′) is a group of the formula:

(R^(e′) and R^(f′) are the same or different and each is a hydrogenatom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorine atom, atrifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group or a hydroxygroup, or R^(e′) and R^(f′) attach to the same carbon atom, then thesegroups may combine together with said carbon atom to form a spiro ring,and Z is a carbon atom, an oxygen atom or a sulfur atom), R^(5′) is ahydrogen atom, a halogen atom, a C₁₋₃ alkyl group, a trifluoromethylgroup, a C₁₋₃ alkoxy group, a trifluoromethoxy group or an aryl group,or R^(4′) and R^(5′) may combine together with the benzene ring to whichthey bond, and form a tetralone ring or an indole ring, which issubstituted by one group selected from a C₁₋₈ alkyl, an aryl-C₁₋₃ alkyl,a C₃₋₇ cycloalkyl-C₁₋₃ alkyl, an arylsulfonyl, a C₁₋₈ alkylidene, a C₁₋₈alkenylidene, an aryl-C₁₋₃ alkylidene and a C₃₋₇ cycloalkyl-C₁₋₃alkylidene, or a pharmaceutically acceptable salt thereof, or a hydrateor solvate thereof.
 3. An N-arylphenylacetamide derivative of theformula (Ia):

wherein R¹¹ is a C₁₋₄ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group, a C₁₋₆ alkylsulfonylamino group or anarylsulfonylamino group, R²¹ is a hydrogen atom, a C₁₋₆ alkylcarbonylgroup, an arylcarbonyl group or —(CH₂)₂—N(R⁶²)(R⁷²), in which R⁶² is ahydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group, anamino-C₂₋₃ alkyl group, a formyl group, or an aryl-C₁₋₃ alkyloxycarbonylgroup, R⁷² is a hydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkylgroup or an amino-C₂₋₃ alkyl group, R³¹ is a hydrogen atom, a halogenatom, a C₁₋₄ alkyl group or an aryl group, R⁴¹ is a C₆₋₁₀ alkyl group; amonocyclic group or a polycyclic group consisting of a 5- or 6-memberedaromatic ring containing 0 to 3 heteroatoms selected from N, O and S,which may optionally be substituted by 1 to 3 atoms or groups selectedfrom a halogen, a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, a trifluoromethyl, atrifluoroethyl, an aryl, an aryl-C₁₋₃ alkyl, a C₁₋₃ alkoxy, atrifluoromethoxy, an aryloxy, a C₁₋₃ alkylcarbonyl, a C₃₋₇cycloalkylcarbonyl, a nitro, a cyano, a hydroxy, a C₁₋₃ alkylthio, aC₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, a carboxy-C₁₋₃ alkyl, a C₁₋₄alkoxycarbonyl and carboxyl; a C₅₋₇ cycloalkenyl group which mayoptionally be substituted by 1 to 4 atoms or groups selected from a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a fluorine, a trifluoromethyl, an aryl, a C₁₋₃alkoxy and a hydroxy; a group of the formula (B′):

(R^(a′), R^(b′), R^(c′) and R^(d′) are the same or different and each isa hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorineatom, a trifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group or ahydroxy group, or when R^(a′) and R^(b′) attach to the same carbon atom,then these groups may combine to form an oxo group, or when R^(c′) andR^(d′) attach to the same carbon atom, then these groups may combinetogether with said carbon atom to form a spiro ring, or 2 or 3 groupsselected from R^(a′), R^(b′) and R^(c′) may combine to form a C₆₋₁₅polycycloalkyl group, and n′ is an integer of 1 to 5); or a group of theformula (C′):

(R^(e′) and R^(f′) are the same or different and each is a hydrogenatom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorine atom, atrifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group, or a hydroxygroup, or when R^(e′) and R^(f′) attach to the same carbon atom, thenthese groups may combine together with said carbon atom to form a spiroring, and Z is a carbon atom, an oxygen atom or a sulfur atom), R⁵¹ is ahydrogen atom, a halogen atom, a C₁₋₃ alkyl group, a trifluoromethylgroup, a C₁₋₃ alkoxy group, a trifluoromethoxy group or an aryl group,or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.
 4. The N-arylphenylacetamide derivative according to claim 3,wherein R¹¹ is a methoxy group, R²¹ is a hydrogen atom, an acetyl group,an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonylgroup, a butylcarbonyl group, a tert-butylcarbonyl group, a benzoylgroup or a 2-aminoethyl group, R³¹ is a hydrogen atom or a iodine atom,R⁴¹ is a phenyl group, a naphthyl group, a thienyl group, a pyrrolylgroup, a benzo[d]-1,3-dioxolanyl group, a benzo[b]furanyl group, abenzo[b]thiophenyl group or a dibenzo[b,d]furanyl group, which mayoptionally be substituted by 1 to 3 atoms or groups selected from afluorine, a chlorine, a methyl, an ethyl, a propyl, an isopropyl, atert-butyl, a cyclopentyl, a cyclohexyl, a trifluoromethyl, a phenyl, afluorophenyl, a chlorophenyl, a methylphenyl, a trifluoromethylphenyl, atrifluoromethoxyphenyl, a trifluoromethoxy, a methylthio, amethoxycarbonyl, an ethoxycarbonyl, a tert-butoxycarbonyl and acarboxyl; or a cyclohexenyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group, a bicyclo[2,2,2]octyl group, an adamantylgroup, a 1-piperidinyl group, a 7-azaspiro[4,5]decan-7-yl group, a2-azaspiro[5,5]-undecan-2-yl group, a 1-azaspiro[5,5]undecan-1-yl group,a 4-morpholinyl group, a 4-thiomorpholinyl group or a1-oxa-4-azaspiro-[5,5]undecan-4-yl group, which may optionally besubstituted by 1 to 4 atoms or groups selected from a methyl, an ethyl,a propyl, an isopropyl, a tert-butyl, a cyclopentyl, a cyclohexyl, afluorine, a trifluoromethyl, a phenyl, a fluorophenyl, a chlorophenyl, amethylphenyl, a trifluoromethylphenyl and a trifluoromethoxyphenyl, R⁵¹is a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethylgroup, a methoxy group, a trifluoromethoxy group or a phenyl group, or apharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.
 5. An N-arylphenylacetamide derivative of the formula (Ib):

wherein R¹¹ is a C₁₋₄ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group, a C₁₋₆ alkylsulfonylamino group, or anarylsulfonylamino group, R²¹ is a hydrogen atom, a C₁₋₆ alkylcarbonylgroup, an arylcarbonyl group or —(CH₂)₂—N(R⁶²)(R⁷²), in which R⁶² is ahydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group, anamino-C₂₋₃ alkyl group, a formyl group, or an aryl-C₁₋₃ alkyloxycarbonylgroup, and R⁷² is a hydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃alkyl group or an amino-C₂₋₃ alkyl group, R³¹ is a hydrogen atom, ahalogen atom, a C₁₋₄ alkyl group or an aryl group, Y″ is —CH₂—,—(CH₂)₂—, —(CH₂)₃—, —CH═CH—, —C≡C—, —CO—, —COCH₂—, —CO(CH₂)₂—,—COCH═CH—, —O— or —O(CH₂)₂—, R⁸¹ is a monocyclic group or a polycyclicgroup consisting of a 5- or 6-membered aromatic ring containing 0 to 3heteroatoms selected from N, O and S, which may optionally besubstituted by 1 to 3 atoms or groups selected from a halogen, a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a trifluoromethyl, a trifluoroethyl, an aryl,an aryl-C₁₋₃ alkyl, a C₁₋₃ alkoxy, a trifluoromethoxy, an aryloxy, aC₁₋₃ alkylcarbonyl, a C₃₋₇ cycloalkylcarbonyl, a nitro, a cyano, ahydroxy, a C₁₋₃ alkylthio, a C₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, acarboxy-C₁₋₃ alkyl, a C₁₋₄ alkoxycarbonyl and a carboxyl; a C₅₋₇cycloalkenyl group which may optionally be substituted by 1 to 4 atomsor groups selected from a C₁₋₆ alkyl, a C₃₋₇ cycloalkyl, a fluorine, atrifluoromethyl, an aryl, a C₁₋₃ alkoxy and a hydroxy; or a group of theformula (B′):

(R^(a′), R^(b′), R^(c′) and R^(d′) are the same or different and each isa hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a fluorineatom, a trifluoromethyl group, an aryl group, a C₁₋₃ alkoxy group or ahydroxy group, or when R^(a′) and R^(b′) attach to the same carbon atom,then these groups may combine to form an oxo group, or when R^(c′) andR^(d′) attach to the same carbon atom, then these groups may combinetogether with said carbon atom to form a spiro ring, or 2 or 3 groupsselected from R^(a′), R^(b′) and R^(c′) may combine to form a C₆₋₁₅polycycloalkyl group, and n′ is an integer of 1 to 5), R⁵¹ is a hydrogenatom, a halogen atom, a C₁₋₃ alkyl group, a trifluoromethyl group, aC₁₋₃ alkoxy group, a trifluoromethoxy group or an aryl group, or apharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.
 6. The N-arylphenylacetamide derivative according to claim 5,wherein R¹¹ is a methoxy group, R²¹ is a hydrogen atom, an acetyl group,an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonylgroup, a butylcarbonyl group, a tert-butylcarbonyl group, a benzoylgroup, a 2-aminoethyl group, R³¹ is a hydrogen atom or a iodine atom, Y″is —(CH₂)₂—, —CH═CH—, —C≡C—, —O— or —O(CH₂)₂—, R⁸¹ is a phenyl group, anaphthyl group or a thienyl group, which may optionally be substitutedby 1 to 3 atoms or groups selected from a fluorine, a chlorine, amethyl, an ethyl, a propyl, an isopropyl, a tert-butyl, a cyclopentyl, acyclohexyl, a trifluoromethyl, a phenyl, a fluorophenyl, a chlorophenyl,a methylphenyl, a trifluoromethylphenyl, a trifluoromethoxyphenyl, atrifluoromethoxy, a methylthio and a methoxycarbonyl; or a cyclohexenylgroup, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, abicyclo[2,2,2]octyl group or an adamantyl group, which may optionally besubstituted by 1 to 4 atoms or groups selected from a methyl, an ethyl,a propyl, an isopropyl, a tert-butyl, a cyclopentyl, a cyclohexyl, afluorine, a trifluoromethyl, a phenyl, a fluorophenyl, a chlorophenyl, amethylphenyl, a trifluoromethylphenyl and a trifluoromethoxyphenyl, R⁵¹is a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethylgroup, a methoxy group, a trifluoromethoxy group or a phenyl group, or apharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.
 7. An N-arylphenylacetamide derivative of the formula (Ic):

wherein R¹¹ is a C₁₋₄ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group, a C₁₋₆ alkylsulfonylamino group or anarylsulfonylamino group, R²¹ is a hydrogen atom, a C₁₋₆ alkylcarbonylgroup, an arylcarbonyl group or —(CH₂)₂—N(R⁶²)(R⁷²), in which R⁶² is ahydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃ alkyl group, anamino-C₂₋₃ alkyl group, a formyl group or an aryl-C₁₋₃ alkyloxycarbonylgroup, and R⁷² is a hydrogen atom, a C₁₋₃ alkyl group, a hydroxy-C₂₋₃alkyl group or an amino-C₂₋₃ alkyl group, R³¹ is a hydrogen atom, ahalogen atom, a C₁₋₄ alkyl group or an aryl group, R⁴² and R⁵² maycombine together with the benzene ring to which they bond to form agroup selected from the following group:

(R⁹¹ is a C₁₋₈ alkyl group; an aryl-C₁₋₃ alkyl group; a C₃₋₇cycloalkyl-C₁₋₃ alkyl group; or an arylsulfonyl group, R⁹² is a C₁₋₇alkyl group; a C₁₋₇ alkenyl group; a phenyl group which may optionallybe substituted by 1 to 3 atoms or groups selected from a halogen, a C₁₋₆alkyl, a C₃₋₇ cycloalkyl, a trifluoromethyl, a trifluoroethyl, an aryl,an aryl-C₁₋₃ alkyl, a C₁₋₃ alkoxy, a trifluoromethoxy, an aryloxy, aC₁₋₃ alkylcarbonyl, a C₃₋₇ cycloalkylcarbonyl, a nitro, a cyano, ahydroxy, a C₁₋₃ alkylthio, a C₁₋₄ alkoxycarbonyl-C₁₋₃ alkyl, acarboxy-C₁₋₃ alkyl, a C₁₋₄ alkoxycarbonyl and a carboxyl; an aryl-C₁₋₂alkyl group; a C₃₋₇ cycloalkyl group; or a C₃₋₇ cycloalkyl-C₁₋₂ alkylgroup), or a pharmaceutically acceptable salt thereof, or a hydrate orsolvate thereof.
 8. The N-arylphenylacetamide derivative according toclaim 7, wherein R¹¹ is a methoxy group, R²¹ is a hydrogen atom, anacetyl group, an ethylcarbonyl group, a propylcarbonyl group, anisopropylcarbonyl group, a butylcarbonyl group, a tert-butylcarbonylgroup, a benzoyl group, a 2-aminoethyl group, R³¹ is a hydrogen atom ora iodine atom, R⁴² and R⁵² may combine together with the benzene ring towhich they bond to form a group selected from the following group:

(R⁹³ is a butyl group, a pentyl group, a hexyl group, an isobutyl group,a heptyl group, or a benzyl group, a phenethyl group or a phenylpropylgroup, wherein the benzene ring moiety may optionally be substituted by1 to 3 atoms or groups selected from a fluorine, a chlorine, a methyl,an ethyl, a propyl, an isopropyl, a tert-butyl, a cyclohexyl, atrifluoromethyl, a phenyl, a fluorophenyl, a chlorophenyl, amethylphenyl, a trifluoromethylphenyl, a trifluoromethoxyphenyl, atrifluoromethoxy, a methylthio and a methoxycarbonyl, and R⁹⁴ is anisopropyl group, or a phenyl group which may optionally be substitutedby 1 to 3 atoms or groups selected from a fluorine, a chlorine, amethyl, an ethyl, a propyl, an isopropyl, a tert-butyl, a cyclohexyl, atrifluoromethyl, a phenyl, a fluorophenyl, a chlorophenyl, amethylphenyl, a trifluoromethylphenyl, a trifluoromethoxyphenyl, atrifluoromethoxy, a methylthio and a methoxycarbonyl), or apharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.
 9. The N-arylphenylacetamide derivative according to claim 1,wherein R² is a hydrogen atom, or a pharmaceutically acceptable saltthereof, or a hydrate or solvate thereof.
 10. The N-arylphenylacetamidederivative according to claim 1, wherein R² is a C₁₋₆ alkylcarbonylgroup or an arylcarbonyl group, or a pharmaceutically acceptable saltthereof, or a hydrate or solvate thereof.
 11. The N-arylphenylacetamidederivative according to claim 1, wherein R² is —(CH₂)₂—N(R⁶)(R⁷), or apharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.
 12. The N-arylphenylacetamide derivative according to claim 1,wherein R² is —(CH₂)_(m)OH or —(CH₂)_(q)COOH, or a pharmaceuticallyacceptable salt thereof, or a hydrate or solvate thereof.
 13. AnN-arylphenylacetamide derivative selected from the following compounds:N-(3-cyclohexylphenyl)-4-hydroxy-3-methoxyphenylacetamide,N-[3-(adamantan-2-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,N-(3-cyclopentylphenyl)-4-hydroxy-3-methoxyphenylacetamide,N-[3-(cyclohexylmethyl) phenyl]-4-hydroxy-3-methoxyphenylacetamide,N-[3-(cyclohexen-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,4-hydroxy-3-methoxy-N-[3-(2-phenylcyclohexan-1-yl)phenyl]-phenylacetamide,4-hydroxy-3-methoxy-N-[3-(4-methylcyclohexan-1-yl)phenyl]-phenylacetamide,N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,4-hydroxy-3-methoxy-N-(3-phenylphenyl)phenylacetamide,4-hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]phenylacetamide,4-hydroxy-3-methoxy-N-[3-(2-phenylethyl) phenyl]phenylacetamide,4-hydroxy-3-methoxy-N-[3-[(Z)-2-phenylvinyl]phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(2-phenylethyl)phenyl]phenylacetamide,4-(2-aminoethoxy)-N-(3-cyclohexylphenyl)-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-(3-phenylphenyl)phenylacetamide,4-(2-aminoethoxy)-N-[3-(3-fluorophenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(4-chlorophenyl)phenyl]-3-methoxyphenylacetamide,4-acetoxy-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide,4-benzoyloxy-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide,4-tert-butylcarbonyloxy-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide,N-[3-(4-tert-butylcyclohexen-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,4-hydroxy-3-methoxy-N-[3-(4-trifluoromethylcyclohexan-1-yl)-phenyl]phenylacetamide,4-hydroxy-3-methoxy-N-[3-(3-methylcyclohexan-1-yl)phenyl]-phenylacetamide,N-[3-(2,6-dimethylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,N-[3-(3,5-dimethylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,N-[3-(4-tert-butylpiperidin-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,N-[3-(3-cyclohexylpiperidin-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,N-[3-(3-methylpiperidin-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide,N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-5-iodo-3-methoxyphenylacetamide,4-hydroxy-3-methoxy-N-[3-(2-chlorothiophen-5-yl)phenyl]-phenylacetamide,4-hydroxy-3-methoxy-N-[3-(1-tert-butoxycarbonylpyrrol-2-yl)-phenyl]phenylacetamide,4-hydroxy-3-methoxy-N-[3-(2-cyclohexylethyl)phenyl]phenylacetamide,4-(2-aminoethoxy)-N-[3-(2-cyclohexylphenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(2-fluorophenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(4-fluorophenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(2-chlorophenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(3-chlorophenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(3,5-difluorophenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(2-methylphenyl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(2,4,6-trimethylphenyl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-N-[3-(3-isopropylphenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(4-trifluoromethylphenyl)-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(2-trifluoromethylphenyl)-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(2-phenylphenyl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(3-phenylphenyl)phenyl]phenylacetamide,4-(2-aminoethoxy)-N-[3-(3-methoxycarbonylphenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(3-trifluoromethoxyphenyl)-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(2-methylthiophenyl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(thiophen-3-yl)phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(naphthalen-1-yl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-N-[3-(2H-benzo[d]-1,3-dioxolan-5-yl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(benzofuran-2-yl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(3-tert-butylphenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[(2-fluoro-5-phenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[(2-methoxy-3-fluoro-5-phenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[(2-methyl-5-phenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[(3-phenyl-4-methyl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[(2-methoxy-5-phenyl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[(3-trifluoromethyl-5-phenyl)-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[(3-phenyl-4-trifluoromethoxy)-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[(4-methyl-3,5-diphenyl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-N-[3-(3-cyclohexylphenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-(2-tert-butylphenyl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(3-phenoxyphenyl)phenyl]-phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(2-phenylethyloxy)phenyl]-phenylacetamide,4-(2-aminoethoxy)-N-[3-[(cis)-4-tert-butylcyclohexan-1-yl]phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-N-[3-[(trans)-4-tert-butylcyclohexan-1-yl]-phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(piperidin-1-yl)phenyl]phenylacetamide,4-(2-aminoethoxy)-N-[3-(3-cyclohexylpiperidin-1-yl)phenyl]-3-methoxyphenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(3-phenylpiperidin-1-yl)-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-(2-azaspiro[5,5]undecan-2-yl)-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-[2-(3-methylphenyl)ethyl]-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[3-[2-(2-fluorophenyl)ethyl]-phenyl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[1-oxo-2-phenylmethyl-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide,4-(2-aminoethoxy)-3-methoxy-N-[1-benzylindol-6-yl]phenylacetamide, and4-hydroxy-3-methoxy-N-[1-oxo-2-phenylmethyl-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide,or a pharmaceutically acceptable salt thereof, or a hydrate or solvatethereof.
 14. A pharmaceutical composition, which comprises as an activeingredient the N-arylphenylacetamide derivative as set forth in any oneof claims 1 to 13, or a pharmaceutically acceptable salt thereof, or ahydrate or solvate thereof.
 15. An analgesic agent or anantiinflammatory agent, which comprises as an active ingredient theN-arylphenylacetamide derivative as set forth in any one of claims 1 to13, or a pharmaceutically acceptable salt thereof, or a hydrate orsolvate thereof.
 16. A method for treatment of pain or inflammation,which comprises administering an effective amount of theN-arylphenylacetamide derivative as set forth in any one of claims 1 to13, or a pharmaceutically acceptable salt thereof, or a hydrate orsolvate thereof, to a patient having a pain or an inflammation.